Cannabinoid receptor antagonists/inverse agonists useful for treating metabolic disorders, including obesity and diabetes

ABSTRACT

The present invention provides novel pyrazoles that are useful as cannabinoid receptor antagonists and pharmaceutical compositions thereof and methods of using the same for treating obesity, diabetes, and/or cardiometabolic disorders.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application claims priority benefit under 35 U.S.C. §19(e) of U.S. Provisional Patent Application Ser. No. 60/798,001 filed May 5, 2006. The disclosure this application is incorporated herein by reference.

FIELD OF THE INVENTION

The present invention provides cannabinoid receptor antagonists/inverse agonists and pharmaceutical compositions thereof and methods of using the same for treating obesity, diabetes, and/or cardiometabolic disorders. The present invention also relates to a novel method for treating obesity, diabetes, and/or cardiometabolic disorders using a pyrazoline.

BACKGROUND OF THE INVENTION

Obesity is associated with an increase in the overall amount of adipose tissue (i.e., body fat), especially adipose tissue localized in the abdominal area. Obesity has reached epidemic proportions in the United States. The prevalence of obesity has steadily increased over the years among all racial and ethnic groups. The most recent data from the Centers for Disease Control and Prevention, and the National Center for Health Statistics report 66% of the adult population overweight (BMI, 25.0-29.9), 31% obese (BMI, 30-39.9), and 5% extremely obese (BMI, ≧40.0). Among children aged 6 through 19 years, 32% are reported as overweight and 17% as obese. This translates to 124 million Americans medically overweight, and 44 million of these deemed obese. Obesity is responsible for more than 300,000 deaths annually, and is one of the leading causes of preventable death in the United States. Obesity is a chronic disease that contributes directly to numerous dangerous co-morbidities, including type 2 diabetes, cardiovascular disease, inflammatory diseases, premature aging, and some forms of cancer. Type 2 diabetes, a serious and life-threatening disorder with growing prevalence in both adult and childhood populations, is currently the 7^(th) leading cause of death in the United States. Since more than 80% of patients with type 2 diabetes are overweight, obesity is the greatest risk factor for developing type 2 diabetes. Increasing clinical evidence indicates that the best way to control type 2 diabetes is to reduce weight.

The most popular over-the counter drugs for the treatment of obesity, phenylpropanolamine and ephedrine, and the most popular prescription drug, fenfluramine, were removed from the marketplace as a result of safety concerns. Drugs currently approved for the long-term treatment of obesity fall into two categories: (a) CNS appetite suppressants such as sibutramine and (b) gut lipase inhibitors such as orlistat. CNS appetite suppressants reduce eating behavior through activation of the ‘satiety center’ in the brain and/or by inhibition of the ‘hunger center’ in the brain. Gut lipase inhibitors reduce the absorption of dietary fat from the gastrointestinal (GI) tract. Although sibutramine and orlistat work through very different mechanisms, they share in common the same overall goal of reducing body weight secondary to reducing the amount of calories that reach the systemic circulation. Unfortunately, these indirect therapies produce only a modest initial weight loss (approximately 5% compared to placebo) that is usually not maintained. After one or two years of treatment, most patients return to or exceed their starting weight. In addition, most approved anti-obesity therapeutics produce undesirable and often dangerous side effects that can complicate treatment and interfere with a patient's quality of life.

The lack of therapeutic effectiveness, coupled with the spiraling obesity epidemic, positions the ‘treatment of obesity’ as one of the largest and most urgent unmet medical needs. There is, therefore, a real and continuing need for the development of improved medications that treat or prevent obesity.

The endocanabinoid system, comprised of the canabinoid receptors (CB 1 and CB2) and their endogenous ligands (e.g., anandamide, 2-AG), plays a prominent role in the control of food intake and energy metabolism. CB 1 receptors are widely expressed in the brain, including cortex, hippocampus, amygdala, pituitary and hypothalamus. CB 1 receptors have also been identified in numerous peripheral organs and tissues, including thyroid gland, adrenal gland, reproductive organs, adipose tissue, liver, muscle, and gastrointestinal tract. CB2 receptors are localized almost exclusively in immune and blood cells, see Endocrine Reviews 2006, 27, 73.

The plant-derived cannabinoid agonist Δ⁹-tetrahydrocannabinol (Δ⁹-THC), the main psychoactive component of marijuana, binds to both CB1 and CB2 receptors. Δ⁹-THC is widely reported to increase appetite and food intake (hyperphagia) in humans and in animals. This hyperphagic effect is largely blocked by pretreatment with selective CB1 receptor antagonists/inverse agonists [e.g., rimonabant (SR141716A, Acomplia®)], strongly supporting the belief that CB1 receptor activation mediates the hyperphagic effect of Δ⁹-THC, see Endocrine Reviews 2006, 27, 73.

In humans, rimonabant produces a clinically meaningful weight loss in obese patients. Patients also experience improvements in diabetes and in associated cardiometabolic risk factors, including a decrease in triglyceride levels. Rimonabant also produces greater reductions in abdominal fat deposits, which are a known risk factor for diabetes and heart disease. Taken together, these improvements in adiposity, diabetes, and cardiometabolic risk factors produce an overall decrease in the prevalence of the metabolic syndrome, see Lancet 2005, 365, 1389-97 and NEJM 2005, 353, 2121.

The beneficial effects of rimonabant on diabetes and cardiometabolic risk factors such as high blood pressure and elevated levels of triglycerides cannot be explained by diet and weight loss alone. For example, in patients receiving 20 mg of rimonabant, only approximately 50% of the beneficial effects on triglycerides, fasting insulin, and insulin resistance can be accounted for by weight loss. These results suggest a direct pharmacological effect of CB1 antagonists/inverse agonists on glucose and lipid metabolism, in addition to indirect effects on metabolism secondary to hypophagia-mediated weight loss, see Science 2006, 311, 323 and JAMA 2006, 311, 323.

The CB1 receptor is one of the most abundant and widely distributed G protein-coupled receptors in the mammalian brain. It is believed that the appetite-suppressant properties of CB1 antagonists/inverse agonists are mediated through an interaction with CB1 receptors in the hypothalamus (regulation of food intake), and in the mesolimbic region (rewarding properties of food). However, CB1 receptors are far more broadly distributed in brain (e.g., neocortex, hippocampus, thalamus, cerebellum, and pituitary), and while interacting with targeted CB1 receptors in hypothalamus and mesolimbic regions, CB1 antagonists have ready access to non-targeted CB1 receptors that have little if any role in appetite control. Binding to non-targeted receptors can often lead to unwanted side effects of CNS drugs [Endocrine Reviews 2006, 27: 73]. The CB1 antagonist/inverse agonist rimonabant produces psychiatric and nervous system side effects. These include depressed mood, anxiety, irritability, insomnia, dizziness, and headache. These side effects are dose-related and are most pronounced at the most efficacious weight-reducing dose of rimonabant (JAMA 2006, 311, 323). The occurrence of therapeutic efficacy (appetite suppression) and side effects over the same dose range strongly suggest that both effects are mediated through concurrent antagonism of CB1 receptors in both ‘targeted’ and ‘non-targeted’ brain regions. Brain-penetrant CB1 antagonists do not selectively target CB1 receptors in efficacy brain regions, while ignoring CB1 receptors in side effect brain regions.

The beneficial effects of the CB1 antagonist/inverse agonist rimonabant on body weight, adiposity, diabetes, and cardiometabolic risk factors such as high blood pressure and elevated levels of triglycerides cannot be explained by weight loss derived from CNS-mediated appetite suppression alone, see JAMA 2006, 311, 323. Approximately 50% of the non-CNS benefit is likely derived from an interaction with CB1 receptors in peripheral tissues known to play an active role in metabolism. These include adipose tissue, liver, muscle, and gastrointestinal tract.

In view of the above, it is highly desirable to find effective and highly selective CB1 receptor antagonists/inverse agonists with limited or no CNS adverse side effects, including mood disorders. Particularly, it is desirable to find compounds that preferentially target CB1 receptors in peripheral tissues (e.g., adipose tissue, liver, muscle, and gastrointestinal tract), while sparing CB1 receptors in brain. In this way, peripherally-mediated beneficial effects of CB1 antagonists/invers agonists should be maintained, whereas CNS side effects should be reduced or eliminated. This should provide a novel opportunity to develop safer agents for the prevention or treatment of obesity, diabetes, and cardiometabolic diseases (e.g., hypertension and dyslipidemias).

SUMMARY OF THE INVENTION

Accordingly, in an aspect, the present invention provides novel pyrazolines or pharmaceutically acceptable salts thereof that are CB1 receptor antagonists.

In another aspect, the present invention provides novel pharmaceutical compositions, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt form thereof.

In another aspect, the present invention provides novel methods for treating obesity, diabetes, and/or cardiometabolic disorders (e.g., hypertension and dyslipidemias), comprising: administering to a patient in need thereof a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt form thereof.

In another aspect, the present invention provides processes for preparing novel compounds.

In another aspect, the present invention provides novel compounds or pharmaceutically acceptable salts for use in therapy.

In another aspect, the present invention provides the use of novel compounds for the manufacture of a medicament for the treatment of obesity, diabetes, and/or cardiometabolic disorders.

These and other objects, which will become apparent during the following detailed description, have been achieved by the inventors' discovery that the presently claimed compounds or pharmaceutically acceptable salt forms thereof are expected to be effective CB1 receptor antagonists.

DETAILED DESCRIPTION OF THE INVENTION

All references cited herein are hereby incorporated in their entirety herein by reference.

The present invention is based on the finding that a CB1 receptor antagonist has beneficial effects on body weight, adiposity, diabetes, and cardiometabolic risk factors such as hypertension and dyslipidemias that cannot be explained by weight loss derived from CNS-mediated appetite suppression alone and that this effect is mediated, at least in part, through interaction at peripheral receptors. To this end, the present invention provides compounds that are designed to preferentially target CB1 receptors in peripheral tissues (e.g., adipose tissue, liver, muscle, and gastrointestinal tract), while sparing CB1 receptors in brain. Peripherally-mediated beneficial effects of CB1 antagonists should be maintained, whereas CNS side effects should be reduced or eliminated.

The compounds of the present invention have been designed to have reduced CNS exposure by virtue of their inability or limited ability to penetrate the blood-brain barrier (BBB) or by their participation in active transport systems, thus reducing centrally mediated side-effects, a potential problem with many anti-obesity and anti-diabetic agents. It is expected that the peripherally restricted compounds of the present invention will have no or very limited CNS effects. Thus, their peripherally mediated CB1 antagonistic properties should provide therapeutic agents with greater safety, as previously demonstrated in earlier classes of peripherally restricted agents.

Moreover, if the maximum dosage of a drug used in the treatment of obesity, diabetes, and/or cardiometabolic disorders (e.g., hypertension and dyslipidemias) is limited as a result of CNS side effects (e.g., seizures, depression, anxiety, movement disorders, and hyperactivity), incorporation of a peripherally restricting group in such a drug would lower the brain concentration of the drug relative to the concentration in the systemic circulation, thereby affording the opportunity to increase the dosage employed to treat the peripheral disorder. The increased dosage may provide greater therapeutic efficacy, as well as a more rapid onset of therapeutic action.

In an embodiment, the present invention provides novel compound AA or a stereoisomer or pharmaceutically acceptable salt thereof:

wherein:

X, Y, X′, Y′, X″, and Y″ are independently selected from: H, C₁₆ alkyl, halogen, CF₃, O-C₁₋₆ alkyl, NO₂, NR₂, O(CH₂)_(n)CO₂R, OCH₂CH═CHCO₂R, CH₂O(CH₂)_(n)CO₂R, CH₂OCH₂CH═CHCO₂R, O(CH₂)_(n)PO(OR)₂, CH₂O(CH₂)_(n)PO(OR)₂, NR^(a)(CH₂)_(n)CO₂R, NR^(a)(CH₂)_(n)PO(OR)₂, NR^(a)CH₂CH═CHCO₂R, NR^(a)SO₂CH₃, NR^(a)CO(CH₂)_(n)CO₂R, NR^(a)CO(CH₂)_(n)CONR^(a) ₂, O(CH₂)_(n)C₆H₄CO₂R, O(CH₂)_(n)C₆H₄(CH₂)_(n)CO₂R, CH₂O(CH₂)_(n)C₆H₄CO₂R, O(CH₂)_(n)C₆H₄CONR^(a) ₂, O(CH₂)_(n)C₆H₄(CH₂)_(n)CONH₂, O(CH₂)_(n)C₆H₄-tetrazole, CH₂O(CH₂)_(n)C₆H₄CONH₂, CH₂O(CH₂)_(n)C₆H₄-tetrazole, O(CH₂)_(n)C₆H₄(CH₂)_(n)-tetrazole, NR^(a)(CH₂)_(n)C₆H₄CO₂R, CH₂NR^(a)(CH₂)_(n)C₆H₄CO₂R, NR^(a)(CH₂)_(n)C₆H₄CONR^(a) ₂, CH₂NR^(a)(CH₂)_(n)C₆H₄CONR^(a) ₂, NR^(a)(CH₂)_(n)C₆H₄-tetrazole, CH₂NR^(a)(CH₂)_(n)C₆H₄-tetrazole, C(NH)NH₂, (CH₂)_(n)C(NH)NH₂, O(CH₂)_(n)CONR^(a) ₂, O(CH₂)_(n)C(NH)NH₂, CH₂O(CH₂)_(n)CONR^(a) ₂, NR^(a)(CH₂)_(n)CONR^(a) ₂, OCH₂CH═CHCONH₂, CH₂OCH₂CH═CHCONR^(a) ₂, NR^(a)CH₂CH═CHCONR^(a) ₂, (CH₂)_(m)-tetrazole, O(CH₂)_(n)-tetrazole, O(CH₂CH₂O)_(p)R, NR^(a)(CH₂CH₂O)_(p)R, and SO₂NR^(a)CH₃;

Z is selected from: H, C₁₋₆ alkyl, OH, O—C₁₋₆ alkyl, O(CH₂CH₂O)_(p)R, acetyloxy, propionyloxy, O(CH₂)_(n)CO₂R, OCH₂CH═CHCO₂R, O(CH₂)_(n)PO(OR)₂, O(CH₂)_(n)CONH₂, O(CH₂)_(n)C(NH)NH₂, OCH₂CH═CHCONH₂, O(CH₂)_(n)-phenyl-(CH₂)_(m)CO₂R, and O(CH₂)_(n)-phenyl-(CH₂)_(m)-tetrazole;

Q is selected from: H, C₁₋₆ alkyl, (CH₂)_(n)-aryl, (CH₂)_(n)-heteroaryl, (CH₂)_(n)-tetrazole, CHA(CH₂)_(m)CO₂R, CHA(CH₂)_(m)CONR₂, (CH₂)_(n)-phenyl-(CH₂)_(m)CO₂R, (CH₂)_(n)-phenyl-(CH₂)_(m)CONH₂, and (CH₂)_(n)-phenyl-(CH₂)_(m)-tetrazole;

M is C═O or SO₂;

R is independently selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl;

R^(a) is independently selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl

A is selected from H, C₁₋₆ alkyl, (CH₂)_(m)—C₃₋₆-cycloalkyl, CH₂OH, CH(CH₃)OH, and (CH₂)_(m)-phenyl, wherein phenyl is substituted with 0-3 groups selected from H, C₁₋₄ alkyl, halogen, CF₃, O—C₁₋₄ alkyl, and NO₂;

p is selected from 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12;

m is selected from 0, 1, 2, and 3;

n is selected from 1, 2, and 3; and,

at least one of X, Y, X′, Y′, X″, Y″, Z, or Q is a group, is suitably modified to be a group, or is replaced by a group capable of reducing or limiting the CNS (brain) levels of compound AA.

[1] In an embodiment, the present invention provides novel compound of Formula I or a stereoisomer or pharmaceutically acceptable salt thereof:

wherein:

X, Y, X′, Y′, X″, and Y″ are independently selected from: H, C₁₋₆ alkyl, halogen, CF₃, O—C₁₋₆ alkyl, NO₂, NR₂, O(CH₂)_(n)CO₂R, OCH₂CH═CHCO₂R, CH₂O(CH₂)_(n)CO₂R, CH₂OCH₂CH═CHCO₂R, O(CH₂)_(n)PO(OR)₂, CH₂O(CH₂)_(n)PO(OR)₂, NR^(a)(CH₂)_(n)CO₂R, NR^(a)(CH₂)_(n)PO(OR)₂, NR^(a)CH₂CH═CHCO₂R, NR^(a)SO₂R, NR^(a)CO(CH₂)_(n)CO₂R, NR^(a)CO(CH₂)_(n)CONR^(a) ₂, O(CH₂)_(n)C₆H₄CO₂R, O(CH₂)_(n)C₆H₄(CH₂)_(n)CO₂R, CH₂O(CH₂)_(n)C₆H₄CO₂R, O(CH₂)_(n)C₆H₄CONR^(a) ₂, O(CH₂)_(n)C₆H₄(CH₂)_(n)CONR^(a) ₂, O(CH₂)_(n)C₆H₄-tetrazole, CH₂O(CH₂)_(n)C₆H₄CONR^(a) ₂, CH₂O(CH₂)_(n)C₆H₄-tetrazole, O(CH₂)_(n)C₆H₄(CH₂)_(n)-tetrazole, NR^(a)(CH₂)_(n)C₆H₄CO₂R, CH₂NR^(a)(CH₂)_(n)C₆H₄CO₂R, NR^(a)(CH₂)_(n)C₆H₄(CH₂)_(n)CO₂R, NR^(a)(CH₂)_(n)C₆H₄CONR^(a) ₂, CH₂NR^(a)(CH₂)_(n)C₆H₄CONR^(a) ₂, NR^(a)(CH₂)_(n)C₆H₄(CH₂)_(n)CONR^(a) ₂, NR^(a)(CH₂)_(n)C₆H₄-tetrazole, CH₂NR^(a)(CH₂)_(n)C₆H₄-tetrazole, NR^(a)(CH₂)_(n)C₆H₄(CH₂)_(n)-tetrazole, C(NH)NR₂, (CH₂)_(n)C(NH)NR₂, O(CH₂)_(n)CONR₂, O(CH₂)_(n)C(NH)NR₂, CH₂O(CH₂)_(n)CONR^(a) ₂, NR^(a)(CH₂)_(n)CONR^(a) ₂, OCH₂CH═CHCONR^(a) ₂, CH₂OCH₂CH═CHCONR^(a) ₂, NR^(a)CH₂CH═CHCONR₂, (CH₂)_(m)-tetrazole, O(CH₂)_(n)-tetrazole, O(CH₂CH₂O)_(p)R, NR^(a)(CH₂CH₂O)_(p)R, and SO₂NHCH₃;

Z is selected from: H, C₁₋₆ alkyl, OH, O—C₁₋₆ alkyl, O(CH₂CH₂O)_(p)R, OC(O)—C₁₋₆ alkyl, O(CH₂)_(n)CO₂R, OCH₂CH═CHCO₂R, O(CH₂)_(n)PO(OR)₂, O(CH₂)_(n)CONH₂, O(CH₂)_(n)C(NH)NH₂, OCH₂CH═CHCONH₂, O(CH₂)_(n)-phenyl-(CH₂)_(m)CO₂R, and O(CH₂)_(n)-phenyl-(CH₂)_(m)-tetrazole;

Q is selected from: H, C₁₋₆ alkyl, (CH₂)_(n)-aryl, (CH₂CH₂O)_(p)R, (CH₂)_(n)-heteroaryl, (CH₂)_(n)-tetrazole, —CHA(CH₂)_(m)C(O)NR₂, CHA(CH₂)_(m)CO₂R, (CH₂)_(n)-phenyl-(CH₂)_(m)CO₂R, (CH₂)_(n)-phenyl-(CH₂)_(m)CONH₂, and (CH₂)_(n)-phenyl-(CH₂)_(m)-tetrazole, wherein the heteroaryl, phenyl, and aryl are substituted with 0-3 groups selected from H, C₁₋₄ alkyl, halogen, CF₃, O—C₁₋₄ alkyl, and NO₂;

M is C═O or SO₂;

R is independently selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl;

R^(a) is independently selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl;

A is selected from H, C₁₋₆ alkyl, (CH₂)_(m)C₃₋₆-cycloalkyl, CH₂OH, CH(CH₃)OH, and (CH₂)_(m)-phenyl, wherein the phenyl is substituted with 0-3 groups selected from H, C₁₋₄ alkyl, halogen, CF₃, O—C₁₋₄ alkyl, and NO₂;

p is selected from 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12;

m is selected from 0, 1, 2, and 3; and,

n is selected from 1, 2, and 3;

provided that at least one of the following is satisfied:

(a) at least one of X, Y, X′, Y′, X″, and Y″ is other than H, C₁₋₆ alkyl, halogen, CF₃, O—C₁₋₆ alkyl, NO₂, and NR₂;

(b) Z is other than H, C₁₋₆ alkyl, OH, O—C₁₋₆ alkyl, acetyloxy, and propionyloxy; or,

(c) Q is other than H, C₁₋₆ alkyl, (CH₂)_(n)-heteroaryl, and (CH₂)_(n)-aryl.

It can be desirable for at least one of X, Y, X′, Y′, X″, and Y″ to be other than H, C₁₋₆ alkyl, halogen, CF₃, O—C₁₋₆ alkyl, NO₂, and NR₂.

[2] In another embodiment, the present invention provides novel compounds of formula I or a stereoisomer or pharmaceutically acceptable salt thereof, wherein:

at least one of X, Y, X′, Y′, X″, and Y″ is independently selected from: O(CH₂)_(n)CO₂R, OCH₂CH═CHCO₂R, CH₂O(CH₂)_(n)CO₂R, CH₂OCH₂CH═CHCO₂R, O(CH₂)_(n)PO(OR)₂, CH₂O(CH₂)_(n)PO(OR)₂, NR^(a)(CH₂)_(n)CO₂R, NR^(a)(CH₂)_(n)PO(OR)₂, NR^(a)CH₂CH═CHCO₂R, NR^(a)CO(CH₂)_(n)CONR^(a) ₂, NR^(a)SO₂CH₃, NR^(a)CO(CH₂)_(n)CO₂R, O(CH₂)_(n)C₆H₄CO₂R, O(CH₂)_(n)C₆H₄(CH₂)_(n)CO₂R, CH₂O(CH₂)_(n)C₆H₄CO₂R, O(CH₂)_(n)C₆H₄CONH₂, O(CH₂)_(n)C₆H₄(CH₂)_(n)CONR^(a) ₂, O(CH₂)_(n)C₆H₄-tetrazole, CH₂O(CH₂)_(n)C₆H₄CONH₂, CH₂O(CH₂)_(n)C₆H₄-tetrazole, O(CH₂)_(n)C₆H₂)_(n)-tetrazole, NR^(a)(CH₂)_(n)C₆H₄CO₂R, CH₂NR^(a)(CH₂)_(n)C₆H₄CO₂R, NR^(a)(CH₂)_(n)C₆H₄(CH₂)_(n)CO₂R, NR^(a)(CH₂)_(n)C₆H₄CONR^(a) ₂, CH₂NRa(CH₂)_(n)C₆H₄CONR^(a) ₂, NR^(a)(CH₂)_(n)C₆ ₄(CH₂)_(n)CONR^(a) ₂, NR^(a)(CH₂)_(n)C₆H₄-tetrazole, CH₂NR^(a)(CH₂)_(n)C₆H₄-tetrazole, NR^(a)(CH₂)_(n)C₆H₄(CH₂)_(n)-tetrazole, C(NH)NR₂, (CH₂)_(n)C(NH)NR₂, O(CH₂)_(n)CONR^(a) ₂, O(CH₂)_(n)C(NH)NH₂, CH₂O(CH₂)_(n)CONR^(a) ₂, NR^(a)(CH₂)_(n)CONH₂, OCH₂CH═CHCONR^(a) ₂, CH₂OCH₂CH═CHCONR^(a) ₂, NR^(a)CH₂CH═CHCONR^(a) ₂, (CH₂)_(m)-tetrazole, O(CH₂)_(n)-tetrazole, O(CH₂CH₂O)_(p)R, NR^(a)(CH₂CH₂O)_(p)R, and SO₂NHCH₃;

the other of X, Y, X′, Y′, X″, and Y″ are independently selected from: H, C₁₋₄ alkyl, halogen, CF₃, O—C₁₋₄ alkyl, NO₂, and NR₂;

R is independently selected from H, C₁₋₄ alkyl, C₂₋₄ alkenyl, and C₂₋₄ alkynyl;

R^(a) is independently selected from H, C₁₋₄ alkyl, C₂₋₄ alkenyl, and C₂₋₄ alkynyl;

Z is selected from: H, C₁₋₄ alkyl, OH, O—C₁₋₄ alkyl, acetyloxy, and propionyloxy;

Q is selected from: is selected from H, C₁₋₄ alkyl, (CH₂CH₂O)_(p)R, (CH₂)_(n)-heteroaryl, and (CH₂)_(m)-aryl, wherein the heteroaryl and aryl are substituted with 0-3 groups selected from H, C₁₋₄ alkyl, halogen, CF₃, O—C₁₋₄ alkyl, and NO₂;

M is C═O or SO₂;

p is selected from 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12;

m is independently selected from 0, 1, 2, and 3; and,

n is independently selected from 1, 2, and 3.

[3] In another embodiment, the present invention provides novel compounds of formula I or a stereoisomer or pharmaceutically acceptable salt thereof, wherein:

X, Y, X′, Y′, X″, and Y″ are independently selected from: H, C₁₋₄ alkyl, halogen, CF₃, O—C₁₋₄ alkyl, NO₂, O(CH₂CH₂O)_(p)R, NR^(a)(CH₂CH₂O)_(p)R, and NR₂;

Z is selected from: O(CH₂CH₂O)_(p)R, O(CH₂)_(n)CO₂R, OCH₂CH═CHCO₂R, O(CH₂)_(n)PO(OR)₂, O(CH₂)_(n)CONH₂, O(CH₂)_(n)C(NH)NH₂, OCH₂CH═CHCONH₂, O(CH₂)_(n)-phenyl-(CH₂)_(m)CO₂R, and O(CH₂)_(n)-phenyl-(CH₂)_(m)-tetrazole;

Q is selected from: H, C₁₋₄ alkyl, (CH₂CH₂O)_(p)R, (CH₂)_(n)-heteroaryl, and (CH₂)_(n)-aryl, wherein the heteroaryl and aryl are substituted with 0-3 groups selected from H, C₁₋₄ alkyl, halogen, CF₃, O—C₁₋₄ alkyl, and NO₂;

M is C═O or SO₂;

R is independently selected from H, C₁₋₄ alkyl, C₂₋₄ alkenyl, and C₂₋₄ alkynyl;

p is selected from 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12;

m is independently selected from 0, 1, 2, and 3; and,

n is independently selected from 1, 2, and 3.

[4] In another embodiment, the present invention provides novel compounds of formula I or a stereoisomer or pharmaceutically acceptable salt thereof, wherein:

X, Y, X′, Y′, X″, and Y″ are individually selected from the following: H, C₁₋₄ alkyl, halogen, CF₃, O—C₁₋₄ alkyl, NO₂, O(CH₂CH₂O)_(p)R, NR^(a)(CH₂CH₂O)_(p)R, and NR₂;

Z is selected from: H, C₁₋₄ alkyl, OH, O—C₁₋₄ alkyl, acetyloxy, and propionyloxy;

Q is selected from: —(CH₂)_(n)-tetrazole, —CHA(CH₂)_(m)C(O)NHR, CHA(CH₂)_(m)CO₂R, (CH₂)_(n)-phenyl-(CH₂)_(m)CO₂R, (CH₂)_(n)-phenyl-(CH₂)_(m)CONH₂, (CH₂)_(n)-phenyl-(CH₂)_(m)-tetrazole, and (CH₂CH₂O)_(p)R;

M is C═O or SO₂;

A is selected from H, C₁₋₄ alkyl, (CH₂)_(m)—C₃₋₆-cycloalkyl, CH₂OH, CH(CH₃)OH, (CH₂)_(m)-phenyl, wherein the phenyl is substituted with 0-3 groups selected from H, C₁₋₄ alkyl, halogen, CF₃, O—C₁₋₄ alkyl, and NO₂;

R is independently selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl;

p is selected from 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12;

m is independently selected from 0, 1, 2, and 3; and,

n is independently selected from 1, 2, and 3.

In another embodiment, the present invention provides novel pharmaceutical compositions, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt form thereof.

In another embodiment, the present invention provides a novel method for treating a disease, comprising: administering to a patient in need thereof a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt form thereof, wherein the disease is selected from obesity, diabetes, cardiometabolic disorders, and a combination thereof.

In another embodiment, the diabetes disorder is selected from Type 1 diabetes, Type 2 diabetes, inadequate glucose tolerance, and insulin resistance.

In another embodiment, the cardiometabolic disorder is selected from dyslipidemias (e.g., elevated levels of triglycerides, elevated levels of low-density lipoprotein (“bad” cholesterol), or low levels of high-density lipoprotein (“good” cholesterol”)) and hypertension.

In another embodiment, the present invention provides a novel method for treating a co-morbidity of obesity, comprising: administering to a patient in need thereof a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt form thereof.

In another embodiment, the co-morbidity is selected from diabetes, Metabolic Syndrome, dementia, and heart disease.

In another embodiment, the co-morbidity is selected from hypertension; gallbladder disease; gastrointestinal disorders; menstrual irregularities; degenerative arthritis; venous statis ulcers; pulmonary hypoventilation syndrome; sleep apnea; snoring; coronary artery disease; arterial sclerotic disease; pseudotumor cerebri; accident proneness; increased risks with surgeries; osteoarthritis; high cholesterol; and, increased incidence of malignancies of the ovaries, cervix, uterus, breasts, prostrate, and gallbladder.

In another embodiment, the present invention also provides a method of preventing or reversing the deposition of adipose tissue in a mammal by the administration of a compound of the present invention. By preventing or reversing the deposition of adipose tissue, compound of the present invention are expected to reduce the incidence or severity of obesity, thereby reducing the incidence or severity of associated co-morbidities.

In another embodiment, the present invention provides a compound of the present invention for use in therapy.

In another embodiment, the present invention provides the use of compounds of the present invention for the manufacture of a medicament for the treatment of obesity, diabetes, cardiometabolic disorders, and a combination thereof.

The present invention may be embodied in other specific forms without departing from the spirit or essential attributes thereof. This invention encompasses all combinations of aspects of the invention noted herein. It is understood that any and all embodiments of the present invention may be taken in conjunction with any other embodiment or embodiments to describe additional embodiments. It is also to be understood that each individual element of the embodiments is intended to be taken individually as its own independent embodiment. Furthermore, any element of an embodiment is meant to be combined with any and all other elements from any embodiment to describe an additional embodiment.

The examples provided in the definitions present in this application are non-inclusive unless otherwise stated. They include but are not limited to the recited examples.

The compounds herein described may have asymmetric centers, geometric centers (e.g., double bond), or both. All chiral, diastereomeric, racemic forms and all geometric isomeric forms of a structure are intended, unless the specific stereochemistry or isomeric form is specifically indicated. Compounds of the present invention containing an asymmetrically substituted atom may be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms, by synthesis from optically active starting materials, or through use of chiral auxiliaries. Geometric isomers of olefins, C═N double bonds, or other types of double bonds may be present in the compounds described herein, and all such stable isomers are included in the present invention. Specifically, cis and trans geometric isomers of the compounds of the present invention may also exist and may be isolated as a mixture of isomers or as separated isomeric forms. All processes used to prepare compounds of the present invention and intermediates made therein are considered to be part of the present invention. All tautomers of shown or described compounds are also considered to be part of the present invention.

“Alkyl” includes both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. C₁₋₆ alkyl, for example, includes C₁, C₂, C₃, C₄, C₅, and C₆ alkyl groups. Examples of alkyl include methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, and s-pentyl.

“Alkenyl” includes the specified number of hydrocarbon atoms in either straight or branched configuration with one or more unsaturated carbon-carbon bonds that may occur in any stable point along the chain, such as ethenyl and propenyl. C₂₋₆ alkenyl includes C₂, C₃, C₄, C₅, and C₆ alkenyl groups.

“Alkynyl” includes the specified number of hydrocarbon atoms in either straight or branched configuration with one or more triple carbon-carbon bonds that may occur in any stable point along the chain, such as ethynyl and propynyl. C₂₋₆ Alkynyl includes C₂, C₃, C₄, C₅, and C₆ alkynyl groups.

“Cycloalkyl” includes the specified number of hydrocarbon atoms in a saturated ring, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. C₃₋₈ cycloalkyl includes C₃, C₄, C₅, C₆, C₇, and C8 cycloalkyl groups.

“Cyclic amine” is a hydrocarbon ring wherein one carbon atom of the ring has been replaced by a nitrogen atom. The cyclic amine can be unsaturated, partially saturated, or fully saturated. The cyclic amine can also be bicyclic, tricyclic, and polycyclic. Examples of cyclic amine include pyrrolidine and piperdine.

Halo” or “halogen” refers to fluoro, chloro, bromo, and iodo.

“Counterion” is used to represent a small, negatively charged species, such as chloride, bromide, hydroxide, acetate, and sulfate.

The group “C₆H₄” represents a phenylene.

“Aryl” refers to any stable 6, 7, 8, 9, 10, 11, 12, or 13 membered monocyclic, bicyclic, or tricyclic ring, wherein at least one ring, if more than one is present, is aromatic. Examples of aryl include fluorenyl, phenyl, naphthyl, indanyl, adamantyl, and tetrahydronaphthyl.

“Heteroaryl” refers to any stable 5, 6, 7, 8, 9, 10, 11, or 12 membered monocyclic, bicyclic, or tricyclic heterocyclic ring that is aromatic, and which consists of carbon atoms and 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of N, O, and S. If the heteroaryl group is bicyclic or tricyclic, then at least one of the two or three rings must contain a heteroatom, though both or all three may each contain one or more heteroatoms. If the heteroaryl group is bicyclic or tricyclic, then only one of the rings must be aromatic. The N group may be N, NH, or N-substituent, depending on the chosen ring and if substituents are recited. The nitrogen and sulfur heteroatoms may optionally be oxidized (e.g., S, S(O), S(O)₂, and N—O). The heteroaryl ring may be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure. The heteroaryl rings described herein may be substituted on carbon or on a nitrogen atom if the resulting compound is stable.

Examples of heteroaryl includes acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzoxazolinyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isatinoyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxindolyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathinyl, phenoxazinyl, phthalazinyl, pteridinyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrazolyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, and xanthenyl.

“Mammal” and “patient” cover warm blooded mammals that are typically under medical care (e.g., humans and domesticated animals). Examples include feline, canine, equine, bovine, and human, as well as just human.

“Treating” or “treatment” covers the treatment of a disease-state in a mammal, and includes: (a) preventing the disease-state from occurring in a mammal, in particular, when such mammal is predisposed to the disease-state but has not yet been diagnosed as having it; (b) inhibiting the disease-state, i.e., arresting it development; and/or (c) relieving the disease-state, i.e., causing regression of the disease state until a desired endpoint is reached.

“Pharmaceutically acceptable salts” refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include, but are not limited to, those derived from inorganic and organic acids selected from 1, 2-ethanedisulfonic, 2-acetoxybenzoic, 2-hydroxyethanesulfonic, acetic, ascorbic, benzenesulfonic, benzoic, bicarbonic, carbonic, citric, edetic, ethane disulfonic, ethane sulfonic, fumaric, glucoheptonic, gluconic, glutamic, glycolic, glycollyarsanilic, hexylresorcinic, hydrabamic, hydrobromic, hydrochloric, hydroiodide, hydroxymaleic, hydroxynaphthoic, isethionic, lactic, lactobionic, lauryl sulfonic, maleic, malic, mandelic, methanesulfonic, napsylic, nitric, oxalic, pamoic, pantothenic, phenylacetic, phosphoric, polygalacturonic, propionic, salicyclic, stearic, subacetic, succinic, sulfamic, sulfanilic, sulfuric, tannic, tartaric, and toluenesulfonic.

The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound that contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are useful. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 18th ed., Mack Publishing Company, Easton, Pa., 1990, p 1445, the disclosure of which is hereby incorporated by reference.

“Therapeutically effective amount” includes an amount of a compound of the present invention that is effective when administered alone or in combination to treat obesity or another indication listed herein. “Therapeutically effective amount” also includes an amount of the combination of compounds claimed that is effective to treat the desired indication. The combination of compounds can be a synergistic combination. Synergy, as described, for example, by Chou and Talalay, Adv. Enzyme Regul. 1984, 22:27-55, occurs when the effect of the compounds when administered in combination is greater than the additive effect of the compounds when administered alone as a single agent. In general, a synergistic effect is most clearly demonstrated at sub-optimal concentrations of the compounds. Synergy can be in terms of lower cytotoxicity, increased effect, or some other beneficial effect of the combination compared with the individual components.

Obesity is defined as having a body mass index (BMI) of 30 or above. The index is a measure of an individual's body weight relative to height. BMI is calculated by dividing body weight (in kilograms) by height (in meters) squared. Normal and healthy body weight is defined as having a BMI between 20 and 24.9. Overweight is defined as having a BMI ≧25. Obesity has reached epidemic proportions in the U.S., with 44 million obese Americans, and an additional eighty million deemed medically overweight.

Obesity is a disease characterized as a condition resulting from the excess accumulation of adipose tissue, especially adipose tissue localized in the abdominal area. It is desirable to treat overweight or obese patients by reducing their amount of adipose tissue, and thereby reducing their overall body weight to within the normal range for their sex and height. In this way, their risk for co-morbidities such as diabetes and cardiovascular disease will be reduced. It is also desirable to prevent normal weight individuals from accumulating additional, excess adipose tissue, effectively maintaining their body weights at a BMI <25, and preventing the development of co-morbidities. It is also desirable to control obesity, effectively preventing overweight and obese individuals from accumulating additional, excess adipose tissue, reducing the risk of further exacerbating their co-morbidities.

Cannabinoid receptors are located in a number of peripheral (non-CNS) tissues, including thyroid gland, adrenal gland, reproductive organs, adipose tissue, liver, muscle, and gastrointestinal tract. Cannabinoid receptor antagonists/invers agonists being developed to treat obesity and smoking cessation, regardless of route of administration, enter the CNS from the systemic circulation. While present in the systemic circulation, such drugs have access to peripheral tissues. One of skill in the art recognizes that cannabinoid receptor antagonists intended to enter the CNS from the systemic circulation in order to treat obesity and smoking cessation, also have access to cannabinoid receptors in peripheral tissues. Thus, a cannabinoid receptor antagonist useful for the present invention may have some access to the CNS from the systemic circulation.

Drugs enter the CNS from the systemic circulation by crossing the blood-brain barrier (BBB). The BBB is a highly specialized ‘gate-keeper’ that protects the brain by preventing the entry of many potentially harmful substances into the CNS from the systemic circulation. Much is known about the BBB, and of the physical-chemical properties required for compounds transported across it.

Drugs that do not cross the BBB into the CNS or that are readily eliminated through transport mechanisms (J Clin Invest. 97, 2517(1996)) are known in the literature and have low CNS activity due to their inability to develop brain levels necessary for pharmacological action. The BBB has at least one mechanism to remove drugs prior to their accumulation in the CNS. P-Glycoproteins (P-gp) localized in plasma membrane of the BBB can influence the brain penetration and pharmacological activity of many drugs through translocation across membranes. The lack of accumulation into the brain by some drugs can be explained by their active removal from the brain by P-gp residing in the BBB. For example, the typical opioid drug loperamide, clinically used as an antidiarrheal, is actively removed from the brain by P-gp, thus explaining its lack of opiate-like CNS effects. Another example is domperidone, a dopamine receptor blocker that participates in the P-gp transport (J Clin Invest. 97, 2517(1996)). Whereas dopamine receptor blockers that cross the BBB can be used to treat schizophrenia, the readily-eliminated domperidone can be used to prevent emesis, without the likelihood of producing adverse CNS effects.

In addition to the above compounds, agents possessing structural characteristics that retard or prevent BBB penetration or contribute to participation in active elimination processes have been identified in various classes of therapeutics. These include antihistamines (Drug Metab. Dispos. 31, 312 (2003)), beta-adrenergic receptor antagonists (B-blockers)(Eur. J. Clin. Pharmacol. 28, Suppl: 21-3 (1985); Br. J. Clin. Pharmacol, 11 (6), 549-553 (1981)), non-nucleoside reverse transcriptase inhibitors (NNRTIs)(J. Pharm Sci., 88(10) 950-954 (1999)), and opioid antagonists. This latter group has been tested in relation to their activity in the GI tract. These peripherally selective opioid antagonists are described in various U.S. patents as being useful in the treatment of non-CNS pathologies in mammals, in particular those of the GI tract (see U.S. Pat. No. 5,260,542; U.S. Pat. No. 5,434,171; U.S. Pat. No. 5,159,081; and U.S. Pat. No. 5,270,238).

Other types of non-brain penetrant compounds can be prepared through the creation of a charge within the molecule. Thus, the addition of a methyl group to the tertiary amine functionality of the drugs scopolamine or atropine, unlike the parent molecules, prevents their passage across the BBB through the presence of a positive charge. However, the new molecules (methyl-scopolamine and methyl-atropine) retain their full anticholinergic pharmacological properties. As such, these drugs can also be used to treat peripheral diseases, without the concern of adverse CNS effects. The quaternary ammonium compound methylnaltrexone is also used for the prevention and/or treatment of opioid and non-opioid induced side effects associated with opioid administration.

The discovery that the anti-obesity and anti-diabetic activity of cannabinoid receptor antagonists may in part be mediated by a non-CNS mechanism could make it beneficial for the compounds of the present invention to be peripherally restricted, i.e., have an inability or limited ability to cross the BBB, or be readily eliminated from the brain through active transport systems. It may be desirable for the compounds of the present invention to be peripherally restricted, which in turn will result in no or very limited CNS effects. Compounds that provide peripherally mediated anti-obesity properties should result in therapeutic agents with greater safety, as previously demonstrated in earlier classes of peripherally restricted agents. It can be desirable that the compounds of the present invention, when administered in a therapeutically effective amount, have no or very limited CNS effects. It can also be desirable that the lack of CNS effects is a result of the compounds of the present invention having minimal brain concentrations when administered in therapeutically effective amounts. In this context, minimal brain concentrations means levels that are too low to be therapeutically effective for the treatment of a CNS indication or too low to cause significant or measurable deleterious or undesired side effects.

SLV319 (Compound I when X and X″ are 4-Cl; X′, Y, Y′, Y″, and Z are H; Q is CH₃; and M is SO₂) is a drug that crosses the BBB and is indicated for the treatment of obesity. It is believed that SLV319 works to treat obesity via a CNS mechanism. Compounds like SLV319 and compound AA have been described in various publications including J. Med. Chem. 2004, 47(3), 627 and U.S. Pat. No. 6,476,060. In compound AA, one of X, Y, X′, Y′, X″, Y, Z or Q is a group capable of reducing or limiting the CNS activity of compound AA. This reduced or limited CNS activity occurs via at least one of X, Y, X′, Y′, X″, Y, Z and Q being a group that either limits compound AA's ability to cross the BBB relative to that of SLV319 or enables it to be actively removed from the brain at a rate greater than that of SLV319. Examples of the amount of compound AA present in the brain can include (a) from 50, 55, 60, 65, 70, 75, 80, 85, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, to 100% lower than SLV319, (b) from 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, to 100% lower than SLV319, and (c) from 98, 99, to 100% lower than SLV319, when administered at the same dosage.

The compounds of the present invention are expected to be cannabinoid receptor antagonists or inverse agonists.

An inverse agonist is a compound that not only blocks the action of the endogenous agonist at the receptor, but also exhibits its own activity, which is usually the opposite of that shown by the agonist. Inverse agonists are also effective against certain types of receptors (e.g., certain histamine receptors/GABA receptors), which have intrinsic activity without the interaction of a ligand upon them (also referred to as ‘constitutive activity’).

Most methods of treating obesity are dependent on a significant reduction in energy intake, either by a decrease in food intake (e.g., sibutramine) or by inhibition of fat absorption (e.g., orlistat). In the present invention, it can be desirable for adipose tissue to be significantly reduced in the absence of a significant reduction in food intake. The weight loss, as a result of the present invention, comes from the treatment with a CB1 antagonist, largely independent of appetite and food intake. Examples of the level of food intake during adipose tissue loss include (a) food intake is maintained, increased or about 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20% below the normal range of the subject prior to being treated in accordance with the present invention (i.e., its pre-administration level); (b) food intake is maintained, increased, or about 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15% below its pre-administration level; (c) food intake is maintained, increased or about 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10% below its pre-administration level; and (d) food intake level is maintained, increased or about 0, 1, 2, 3, 4, or 5% below its pre-administration level.

In some cases, loss of adipose tissue can be accompanied by a concomitant loss of lean muscle mass. This is particularly evident in cancer patients who show a wasting of all body tissue components, including adipose tissue and lean muscle mass. In the present invention, however, it can be desirable for body fat to be significantly reduced in the absence of a significant reduction in lean body mass. Adipose tissue loss comes from treatment with a CB1 antagonist, independent of a significant change in lean body mass. Examples of the level of lean body mass during adipose tissue loss include (a) lean body mass is maintained, increased, or is no more than about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30% below the normal range of the subject prior to being treated in accordance with the present invention (i.e., its pre-administration level); (b) lean body mass is maintained, increased, or is no more than about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15% below pre-administration levels; (c) lean body mass is maintained, increased, or is no more than about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10% below pre-administration levels; and (d) lean body mass is maintained, increased, or is no more than about 1, 2, 3, 4, or 5% below pre-administration levels.

In some cases, loss of adipose tissue can be accompanied by a concomitant loss of water mass. This is particularly evident with diet regimens that promote dehydration. In the present invention, it can be desirable for body fat to be significantly reduced in the absence of a significant reduction in water mass. In other words, adipose tissue loss comes from treatment with a CB1 antagonist, independent of a significant change in water mass. Examples of the level of water mass during adipose tissue loss include (a) water mass is maintained, increased, or is no more than about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30% below the normal range of the subject prior to being treated in accordance with the present invention (i.e., its pre-administration level); (b) water mass is maintained, increased, or is no more than about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15% below pre-administration levels; (c) water mass is maintained, increased, or is no more than about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10% below pre-administration levels; and (d) water mass is maintained, increased, or is no more than about 1, 2, 3, 4, or 5% below pre-administration levels.

Sibutramine and orlistat are currently marketed for use in the treatment of obesity. These two compounds achieve weight loss through entirely different mechanisms. Sibutramine, a CNS appetite suppressant, inhibits the neuronal reuptake of serotonin and noradrenaline. Orlistat inhibits gut lipase enzymes that are responsible for breaking down ingested fat.

Cannabinoid receptor antagonists/inverse agonists can promote weight loss through inhibition of peripheral cannabinoid receptors, as well as mechanisms entirely different from appetite suppressants, gut lipase inhibitors, and other agents with similar indications (e.g., serotonin agonists, leptin, fatty acid synthase inhibitors, monoamine oxidase (MAO) inhibitors). Co-administration of a cannabinoid receptor antagonist/inverse agonist together with one or more other agents that are useful for treating the indications described above (e.g., obesity, diabetes, cardiometabolic disorders, and a combination thereof) is expected to be beneficial, by producing, for example, either additive or synergistic effects. Examples of additional agents include an appetite suppressant, a lipase inhibitor, and a MAO inhibitor (e.g., MAO-B, and a combination of MAO-A/B). Therefore, the present invention provides a method of treating obesity, diabetes, and/or cardiometabolic disorders, comprising administering a therapeutically effective amount of a compound of the present invention and a second component effective for treating the desired indication.

Examples of second components include anti-obesity agents, which include, but are not limited to: 1) growth hormone secretagogues; 2) growth hormone secretagogue receptor agonists/antagonists; 3) melanocortin agonists; 4) Mc4r (melanocortin 4 receptor) agonists; 5) .beta.-3 agonists; 7) 5HT2C (serotonin receptor 2C) agonists; 8) orexin antagonists; 9) melanin concentrating hormone antagonists; 10) melanin-concentrating hormone 1 receptor (MCH1R) antagonists; 11) melanin-concentrating hormone 2 receptor (MCH2R) agonist/antagonists; 12) galanin antagonists; 13) CCK agonists; 14) CCK-A (cholecystokinin-A) agonists; 16) corticotropin-releasing hormone agonists; 17) NPY 5 antagonists; 18) NPY 1 antagonists; 19) histamine receptor-3 (H3) modulators; 20) histamine receptor-3 (H3) antagonists/inverse agonists; 21)p-hydroxy steroid dehydrogenase-1 inhibitors (.beta.-HSD-1); 22) PDE (phosphodiesterase) inhibitors; 23) phosphodiesterase-3B (PDE3B) inhibitors; 24) NE (norepinephrine) transport inhibitors; 25) non-selective serotonin/norepinephrine transport inhibitors, such as sibutramine, phentermine, or fenfluramine; 26) ghrelin antagonists; 28) leptin derivatives; 29) BRS3 (bombesin receptor subtype 3) agonists; 30) CNTF (Ciliary neurotrophic factors); 31) CNTF derivatives, such as axokine (Regeneron); 32) monoamine reuptake inhibitors; 33) UCP-1 (uncoupling protein-1), 2, or 3 activators; 34) thyroid hormone .beta. agonists; 35) FAS (fatty acid synthase) inhibitors; 37) DGAT2 (diacylglycerol acyltransferase 2) inhibitors; 38) ACC2 (acetyl-CoA carboxylase-2) inhibitors; 39) glucocorticoid antagonists; 40) acyl-estrogens; 41) lipase inhibitors, such as orlistat (Xenical®); 42) fatty acid transporter inhibitors; 43) dicarboxylate transporter inhibitors; 44) glucose transporter inhibitors; 45) phosphate transporter inhibitors; 46) serotonin reuptake inhibitors; 47) Metformin (Glucophage®); 48) Topiramate (Topimax®); and/or 49) MAO inhibitors.

Examples of MAO inhibitors include Moclobemide; Brofaromine; BW A616U; Ro 41-1049; RS-2232; SR 95191; Harmaline; Harman; Amiflamine; BW 1370U87; FLA 688; FLA 788; Bifemelane; Clorgyline; LY 51641; MDL 72,394; 5-(4-Benzyloxyphenyl)-3-(2-cyanoethyl)-(3H)-1,3,4-oxadiazol-2-one; 5-(4-Arylmethoxyphenyl)-2-(2-cyanoethyl)tetrazoles; Lazabemide; Ro 16-6491; Almoxatone; XB308; RS-1636; RS-1653; NW-1015; SL 340026;. L-selegiline; Rasagiline; Pargyline; AGN 1135; MDL 72,974; MDL 72,145; MDL 72,638; LY 54761; MD 780236; MD 240931; Bifemelane; Toloxatone; Cimoxatone; Iproniazid; Phenelzine; Nialamide; Phenylhydrazine; 1-Phenylcyclopropylamine; Isocarboxazid; and, Tranylcypromine. Additional examples of MAO inhibitors can be found in U.S. A No. 60/696,067 ; U.S. A No. 60/686,585 ; U.S. A No. 60/698,867 and U.S. A No. 60/704,679 , the contents of which are incorporated herein by reference.

Examples of second components useful for treating diabetes include (a) insulin sensitizers including (i) PPAR-γ agonists such as the glitazones (e.g. troglitazone, pioglitazone, englitazone, MCC-555, rosiglitazone), and compounds disclosed in WO97/27857, 97/28115, 97/28137, and 97/27847; and (ii) biguanides such as metformin and phenformin; (b) insulin or insulin mimetics; (c) sulfonylureas such as tolbutamide and glipizide, or related materials; (d) α-glucosidase inhibitors (e.g., acarbose); (e) cholesterol lowering agents such as (i) HMG-CoA reductase inhibitors (lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rivastatin, and other statins), (ii) sequestrants (e.g., cholestyramine, colestipol, and dialkylaminoalkyl derivatives of a cross-linked dextran), (iii) nicotinyl alcohol, nicotinic acid or a salt thereof, (iv) PPAR-α agonists (e.g., fenofibric acid derivatives including gemfibrozil, clofibrate, fenofibrate, and bezafibrate), (v) inhibitors of cholesterol absorption (e.g., β-sitosterol) and acyl CoA:cholesterol acyltransferase inhibitors (e.g., melinamide), and (vi) probucol; (f) PPAR-α/γ agonists; (g) antiobesity compounds (described previously); (h) ileal bile acid transporter inhibitors; and (i) insulin receptor activators.

The compounds of the present invention are expected to be CB1 receptor inhibitors/inverse agonists and are expected to be useful for treating diseases mediated by the CB₁ receptor. The compounds of the present are expected to possess an affinity in vitro for the central and/or peripheral cannabinoid receptors under the experimental conditions described by Devane et al., Molecular Pharmacology, 1988, 34, 605-613. The compounds according to the invention are also expected to possess an affinity for the cannabinoid receptors present on preparations of electrically stimulated isolated organs. These tests can be performed on guinea-pig ileum and on mouse vas deferens according to Roselt et al., Acta Physiologica Scandinavia 1975, 94, 142-144, and according to Nicolau et al., Arch. Int. Pharmacodyn, 1978, 236, 131-136.

CB1 receptor affinities can be determined using membrane preparations of Chinese hamster ovary (CHO) cells in which the human cannabinoid CB1 receptor is stably transfected (Biochem J. 1991, 279, 129-134) in conjunction with [3H]CP-55,940 as radioligand. After incubation of a freshly prepared cell membrane preparation with the [3H]-radioligand, with or without addition of test compound, separation of bound and free ligand is performed by filtration over glass fiber filters. Radioactivity on the filter is measured by liquid scintillation counting. The IC₅₀ values can be determined from at least three independent measurements.

In the present invention, the compound(s) of the present invention can be administered in any convenient manner (e.g., enterally or parenterally). Examples of methods of administration include orally and transdermally. One skilled in this art is aware that the routes of administering the compounds of the present invention may vary significantly. In addition to other oral administrations, sustained release compositions may be favored. Other acceptable routes may include injections (e.g., intravenous, intramuscular, subcutaneous, and intraperitoneal); subdermal implants; and, buccal, sublingual, topical, rectal, vaginal, and intranasal administrations. Bioerodible, non-bioerodible, biodegradable, and non-biodegradable systems of administration may also be used. Examples of oral formulations include tablets, coated tablets, hard and soft gelatin capsules, solutions, emulsions, and suspensions.

If a solid composition in the form of tablets is prepared, the main active ingredient can be mixed with a pharmaceutical vehicle, examples of which include silica, starch, lactose, magnesium stearate, and talc. The tablets can be coated with sucrose or another appropriate substance or they can be treated so as to have a sustained or delayed activity and so as to release a predetermined amount of active ingredient continuously. Gelatin capsules can be obtained by mixing the active ingredient with a diluent and incorporating the resulting mixture into soft or hard gelatin capsules. A syrup or elixir can contain the active ingredient in conjunction with a sweetener, which is preferably calorie-free, an antiseptic (e.g., methylparaben and/or propylparaben), a flavoring, and an appropriate color. Water-dispersible powders or granules can contain the active ingredient mixed with dispersants or wetting agents or with suspending agents such as polyvinylpyrrolidone, as well as with sweeteners or taste correctors. Rectal administration can be effected using suppositories, which are prepared with binders melting at the rectal temperature (e.g., cocoa butter and/or polyethylene glycols). Parenteral administration can be effected using aqueous suspensions, isotonic saline solutions, or injectable sterile solutions, which contain pharmacologically compatible dispersants and/or wetting agents (e.g., propylene glycol and/or polyethylene glycol). The active ingredient can also be formulated as microcapsules or microspheres, optionally with one or more carriers or additives. The active ingredient can also be presented in the form of a complex with a cyclodextrin, for example α-, β-, or γ-cyclodextrin, 2-hydroxypropyl-o-cyclodextrin, and/or methyl-1-cyclodextrin.

The dose of the compound of the present invention administered daily will vary on an individual basis and to some extent may be determined by the severity of the disease being treated (e.g., obesity, diabetes, and cardiometabolic disorders). The dose of the compound of the present invention will also vary depending on the compound administered. Examples of dosages of compounds of the present invention include from about 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 76, 80, 85, 90, 95, to 100 mg/kg of mammal body weight. The compound can be administered in a single dose or in a number of smaller doses over a period of time. The length of time during which the compound is administered varies on an individual basis, and can continue until the desired results are achieved (i.e., reduction of body fat, prevention of a gain in body fat, reduced glucose levels, improved insulin sensitivity). Therapy could, therefore, last from 1 day to weeks, months, or even years depending upon the subject being treated, the desired results, and how quickly the subject responds to treatment in accordance with the present invention.

A possible example of a tablet of the present invention is as follows.

Ingredient mg/Tablet Active ingredient 100 Powdered lactose 95 White corn starch 35 Polyvinylpyrrolidone 8 Na carboxymethylstarch 10 Magnesium stearate 2 Tablet weight 250

A possible example of a capsule of the present invention is as follows.

Ingredient mg/Tablet Active ingredient 50 Crystalline lactose 60 Microcrystalline cellulose 34 Talc 5 Magnesium stearate 1 Capsule fill weight 150

In the above capsule, the active ingredient has a suitable particle size. The crystalline lactose and the microcrystalline cellulose are homogeneously mixed with one another, sieved, and thereafter the talc and magnesium stearate are admixed. The final mixture is filled into hard gelatin capsules of suitable size.

A possible example of an injection solution of the present invention is as follows.

Ingredient mg/Tablet Active substance 1.0 mg 1 N HCl 20.0 μl acetic acid 0.5 mg NaCl 8.0 mg Phenol 10.0 mg 1 N NaOH q.s. ad pH 5 H₂O q.s. ad 1 mL

Synthesis

The compounds of the present invention can be prepared in a number of ways known to one skilled in the art of organic synthesis (e.g., see U.S. Pat. No. 6,476,060 B2, J Med Chem 2004, 47, 627). The compounds of the present invention can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or by variations thereon as appreciated by those skilled in the art. Preferred methods include, but are not limited to, those described below. The reactions are performed in a solvent appropriate to the reagents and materials employed and suitable for the transformations being effected. It will be understood by those skilled in the art of organic synthesis that the functionality present on the molecule should be consistent with the transformations proposed. This will sometimes require a judgment to modify the order of the synthetic steps or to select one particular process scheme over another in order to obtain a desired compound of the invention. It will also be recognized that another major consideration in the planning of any synthetic route in this field is the judicious choice of the protecting group used for protection of the reactive functional groups present in the compounds described in this invention. An authoritative account describing the many alternatives to the trained practitioner is Greene and Wuts (Protective Groups In Organic Synthesis, Wiley and Sons, 1991). All references cited herein are hereby incorporated in their entirety herein by reference.

Scheme 1 shows how to convert 2′-, 3′-, or 4′-(carbo-t-butoxymethoxy)-2-phenylacetophenones, prepared from commercially available 2′-, 3′- or 4′-methoxy-2-phenylacetophenones via O-demethylation using HBr/HOAc or BBr₃/CH₂Cl₂ and alkylation of the resultant phenol with t-butyl bromoacetate in the presence of base, in 37% aqueous formaldehyde containing piperidine under reflux to the corresponding acrylophenones (step a). Treatment of the acrylophenones with hydrazine hydrate in ethanol can produce the 3,4-diarylpyrazolines (step b). The diarylpyrazolines can be further treated with arylsulfonyldithioimidocarbonic acid methyl esters, prepared from the corresponding aryl sulfonamides, CS₂ and Mel (see J. Med Chem., 47, 627 (2004); Chem. Ber. 1966, 99, 2885), in a solvent (e.g., acetonitrile) in the presence of triethylamine at reflux to yield the pyrazole-1-carboximidothioic acid methyl ester (step c). Further exposure of these iminothioethers to an aqueous solution of methylamine and methylene chloride at room temperature should afford the pyrazoline-1-carboxamidines (step d). Hydrolysis of the ester using TFA/CH₂Cl₂ should produce the carboxylic acid (step e).

Scheme 2 describes how 2-(2′-, 3′- or 4′-carbo-t-butoxymethoxyphenyl)acetophenones (prepared similarly to scheme 1) should provide the corresponding acrylophenones (step a). Treatment of the acrylophenones with hydrazine hydrate in ethanol can produce the 3,4-diarylpyrazolines (step b). The diarylpyrazolines can be further treated with arylsulfonyldithioimidocarbonic acid methyl esters in a solvent like acetonitrile in the presence of triethylamine at reflux to yield pyrazole-1-carboximidothioic acid methyl esters (step c). Further exposure of these iminothioethers to an aqueous solution of methylamine and methylene chloride at room temperature should afford the pyrazoline-1-carboxamidines (step d). Hydrolysis of the ester using TFA/CH₂Cl₂ should produce the carboxylic acid (step e).

Scheme 3 shows the conversion of 4′-chloro-2-phenylacetophenone in 37% aqueous formalin and MeOH containing piperidine and acetic acid at reflux that should occur affording the acrylophenone (J. Agric. Food Chem. 1979, 27(2), 406)(step a). Treatment of the acrylophenone with hydrazine hydrate in ethanol can produce the 3,4-diarylpyrazolines (step b). The diarylpyrazolines can be further treated with arylsulfonyldithioimidocarbonic acid methyl esters in a solvent like acetonitrile in the presence of triethylamine at reflux to yield the pyrazole-l-carboximidothioic acid methyl ester (step c). Further exposure of these iminothioethers to beta-alanine t-butyl ester in ethanol and methylene chloride containing triethylamine should yield the pyrazoline-esters (step d). Hydrolysis of the ester using TFA/CH₂Cl₂ should produce the carboxylic acid (step e). Treatment of the ester with anhydrous ammonia in methanol at about 0° to room emperature can afford the carboxamido compound (step f). Alternatively, the iminothioethers can be coupled with other amino acid esters to give adducts (step g) that can be hydrolyzed to the carboxylic acids (step h). These acids may be converted to the carboxamides using oxalyl chloride in dichloroethane followed by anhydrous ammonia, or Boc₂O in pyridine/THF followed by anhydrous ammonia (step i).

Scheme 4 illustrates how oxidation of 4′-chloro-2-phenylacrylophenone in methylene chloride with m-chloroperbenzoic acid should provide the epoxide (step a), which upon treatment with hydrazine hydrate in ethanol solution at about 35-40° C. can give the 3,4-diarylpyrazoline alcohol (step b). The pyrazoline can be protected using di-t-butyl-dicarbonate (t-Boc anhydride) in the presence of a base to give the N-t-BOC-pyrazoline (step c). The carbamate alcohol can then be deprotonated with sodium hydride in a solvent like DMF followed by alkylation with ethyl 4-bromocrotonate to yield the ester (step d). Removal of the t-BOC group can be achieved via treatment with TFA (step e). The pyrazoline can then be reacted with arylsulfonyldithioimidocarbonic acid methyl esters in a solvent like acetonitrile in the presence of triethylamine at reflux to yield the pyrazole-1-carboximidothioic acid methyl ether (step f). Further exposure of these iminothioethers to an aqueous solution of methylamine and methylene chloride at room temperature can afford the pyrazoline-1-carboxamidines (step g), and hydrolysis of the ester using LiOH in aqueous THF solution can produce the carboxylic acid (step h). The carbxoamides can be prepared by treatment of the ester with anhydrous ammonia in alcohol at −20° C. to ambient temperature (step i).

Scheme 5 shows how heating a solution of the 3,4-diarylpyrazoline and S-methylisothiourea in pyridine can form the pyrazoline-1-carboxamidine (step a). Treatment of this amidine with t4-cyanobenzenesulfonyl choride in acetonitrile in the presence of N,N-dimethyl-4-aminopyridine and triethylamine can give the carboxamidine-coupled sulfonamide derivative (step b). Conversion of the nitrile to the phenylcarboxamidine can be accomplished using HCl (gas) in MeOH at 0° C. to room temperature, followed by ammonium carbonate or anhydrous ammonia in MeOH at about 0° C. to room temperature (step c).

Scheme 6 describes how the reaction of a freshly prepared anhydrous acetonitrile solution of 4-chlorobenzoylisothiocyanate, made from 4-chlorobenzoylchloride and ammonium isocyanate (see J Heterocycl. Chem. 1991, 28, 1645), and a 3,4-diarylpyrazoline stirred in the cold can afford the pyrazoline—adduct (step a). Treatment of this thiocarboxamide with amino compounds such as ethyl beta-alanine in the presence of HgCl₂ can produce the benzoyl guanidines (step b). Hydrolysis of the ester using LiOH in aqueous THF solution can produce the carboxylic acid (step c). Further conversion of the acid to the acid chloride followed by treatment with anhydrous ammonia should afford the carboxamide (step d).

Scheme 7 depicts how condensation of a solution of 4′-nitro-2-phenylacetophenone in 37% aqueous formalin and MeOH containing piperidine and acetic acid should afford after heating at reflux, the corresponding acrylophenone (step a). Treatment of the acrylophenone with hydrazine hydrate in ethanol can produce the 3,4-diarylpyrazoline (step b). The pyrazoline can then be reacted with arylsulfonyldithioimidocarbonic acid methyl esters in a solvent like acetonitrile in the presence of triethylamine at reflux to yield the corresponding pyrazole-1-carboximidothioic acid methyl ester (step c). The nitro group can be reduced using sodium dithionite in aqueous basic solution to produce the aniline compound (step d). Acylation of the aniline with ethyl malonyl chloride in the presence of base should produce the amide (step e). Treatment of the amidoester with amines such as methylamine or anhydrous ammonia in a solvent such as methanol or methylene chloride at zero degrees to room temperature should afford the pyrazole-1-carboxamidines with the terminal carboxamido group (step f). Alternatively, the aniline compound can be treated with methanesulfonyl chloride to give the sulfonamide (step g), which upon exposure to an aqueous solution of methylamine and methylene chloride at room temperature should afford the pyrazoline-1-carboxamidines (step h).

Scheme 8 illustrates how treatment of 4′-cyano-2-phenylacrylophenone with hydrazine hydrate in ethanol will produce the 3,4-diarylpyrazoline (step a). The pyrazoline can then be reacted with tri-n-butyltin azide, conveniently prepared in situ by the reaction of one equivalent of sodium azide and one equivalent of tri-n-butyltin chloride (see J. Med. Chem. 1991, 56, 2395), in reluxing toluene or xylene to afford the tri-n-butyltin-tetrazole adduct (step b). The tri-n-butyltin-adduct can be converted to the trityl-tetrazole adduct by treatment with one equivalent of aqueous sodium hydroxide solution and one equivalent of trityl chloride at room temperature (step c). Reaction of this adduct with arylsulfonyldithioimidocarbonic acid methyl esters in a solvent like acetonitrile in the presence of triethylamine at reflux should yield the pyrazole-1-carboximidothioic acid methyl ester (step d). Treatment of the iminothioether with aqueous methylamine and methylene chloride at room temperature should afford the pyrazole-1-carboxamidines (step e). Removal of the trityl group with aqueous TFA in THF at room temperature should yield the unprotected tetrazole (step f).

Scheme 9 shows how to convert 2′-, 3′-, or 4′-polyethoxylated analogs of 2-phenylacetophenones, prepared from commercially available 2′-, 3′- or 4′-methoxy-2-phenylacetophenones via O-demethylation using HBr/HOAc or BBr₃/CH₂Cl₂ and alkylation of the resultant phenols with alkyl-capped or TBDMS-capped halides prepared as described in Nuclear Medicine and Biology, 32, 799 (2005). Treatment of these polyether ketones in 37% aqueous formaldehyde containing piperidine under reflux should give the corresponding acrylophenones (step a). Treatment of the acrylophenones with hydrazine hydrate in ethanol can produce the 3,4-diarylpyrazolines (step b). The diarylpyrazolines can be further treated with arylsulfonyldithioimidocarbonic acid methyl esters, prepared from the corresponding aryl sulfonamides, CS₂ and Mel (see J. Med Chem., 47, 627 (2004); Chem. Ber. 1966, 99, 2885), in a solvent (e.g., acetonitrile) in the presence of triethylamine at reflux to yield the pyrazole-1-carboximidothioic acid methyl ester (step c). Further exposure of these iminothioethers to an aqueous solution of methylamine and methylene chloride at room temperature should afford the pyrazoline-1-carboxamidines (step d). Removal of the TBDMS-capping group using anhydrous tetrabutylammonium fluoride in THF should produce the hydroxyl-PEG analog (step e).

One stereoisomer of a compound of the present invention may be a more potent cannabinoid receptor antagonist than its counterpart(s). Thus, stereoisomers are included in the present invention. When required, separation of the racemic material can be achieved by HPLC using a chiral column or by a resolution using a resolving agent such as described in Wilen, S. H. Tables of Resolving Agents and Optical Resolutions 1972, 308 or using enantiomerically pure acids and bases. A chiral compound of the present invention may also be directly synthesized using a chiral catalyst or a chiral ligand, e.g., Jacobsen, E. Acc. Chem. Res. 2000, 33, 421-431 or using other enantio- and diastereo-selective reactions and reagents known to one skilled in the art of asymmetric synthesis. Examples of stereoisomers include compounds of formula Ia and Ib shown below.

Other features of the invention will become apparent in the course of the following descriptions of exemplary embodiments that are given for illustration of the invention and are not intended to be limiting thereof.

EXAMPLES

Tables 1a-c and 2 show representative examples of the compounds of the present invention. Each example in each table represents an individual species of the present invention.

TABLE 1a

Ex. # X X″ Y″ Z Q M 1. C(NH)NH₂ Cl H H H SO₂ 2. OCH₂-tetrazole Cl H H H SO₂ 3. tetrazole Cl H H H SO₂ 4. NHSO₂CH₃ Cl H H H SO₂ 5. OCH₂CO₂Et Cl H H H SO₂ 6. OCH₂CO₂H Cl H H H SO₂ 7. OCH₂CH═CHCO₂Et Cl H H H SO₂ 8. OCH₂CH═CHCO₂H Cl H H H SO₂ 9. NHCOCH₂CO₂Et Cl H H H SO₂ 10. NHCOCH₂CO₂H Cl H H H SO₂ 11. OCH₂C₆H₄-2-CO₂Et Cl H H H SO₂ 12. OCH₂C₆H₄-3-CO₂Et Cl H H H SO₂ 13. OCH₂C₆H₄-4-CO₂Et Cl H H H SO₂ 14. OCH₂C₆H₄-2-CO₂H Cl H H H SO₂ 15. OCH₂C₆H₄-3-CO₂H Cl H H H SO₂ 16. OCH₂C₆H₄-4-CO₂H Cl H H H SO₂ 17. OCH₂C₆H₄-2-tetrazole Cl H H H SO₂ 18. OCH₂C₆H₄-3-tetrazole Cl H H H SO₂ 19. OCH₂C₆H₄-4-tetrazole Cl H H H SO₂ 20. C(NH)NH₂ H CF₃ H H SO₂ 21. OCH₂-tetrazole H CF₃ H H SO₂ 22. tetrazole H CF₃ H H SO₂ 23. NHSO₂CH₃ H CF₃ H H SO₂ 24. OCH₂CO₂Et H CF₃ H H SO₂ 25. OCH₂CO₂H H CF₃ H H SO₂ 26. OCH₂CH═CHCO₂Et H CF₃ H H SO₂ 27. OCH₂CH═CHCO₂H H CF₃ H H SO₂ 28. NHCOCH₂CO₂Et H CF₃ H H SO₂ 29. NHCOCH₂CO₂H H CF₃ H H SO₂ 30. OCH₂C₆H₄-2-CO₂Et H CF₃ H H SO₂ 31. OCH₂C₆H₄-3-CO₂Et H CF₃ H H SO₂ 32. OCH₂C₆H₄-4-CO₂Et H CF₃ H H SO₂ 33. OCH₂C₆H₄-2-CO₂H H CF₃ H H SO₂ 34. OCH₂C₆H₄-3-CO₂H H CF₃ H H SO₂ 35. OCH₂C₆H₄-4-CO₂H H CF₃ H H SO₂ 36. OCH₂C₆H-2-tetrazole H CF₃ H H SO₂ 37. OCH₂C₆H₄-3-tetrazole H CF₃ H H SO₂ 38. OCH₂C₆H₄-4-tetrazole H CF₃ H H SO₂ 39. CONH₂C(NH)NH₂ Cl H OH H SO₂ 40. OCH₂-tetrazole Cl H OH H SO₂ 41. tetrazole Cl H OH H SO₂ 42. NHSO₂CH₃ Cl H OH H SO₂ 43. OCH₂CO₂Et Cl H OH H SO₂ 44. OCH₂CO₂H Cl H OH H SO₂ 45. OCH₂CH═CHCO₂Et Cl H OH H SO₂ 46. OCH₂CH═CHCO₂H Cl H OH H SO₂ 47. NHCOCH₂CO₂Et Cl H OH H SO₂ 48. NHCOCH₂CO₂H Cl H OH H SO₂ 49. OCH₂C₆H₄-2-CO₂Et Cl H OH H SO₂ 50. OCH₂C₆H₄-3-CO₂Et Cl H OH H SO₂ 51. OCH₂C₆H₄-4-CO₂Et Cl H OH H SO₂ 52. OCH₂C₆H₄-2-CO₂H Cl H OH H SO₂ 53. OCH₂C₆H₄-3-CO₂H Cl H OH H SO₂ 54. OCH₂C₆H₄-4-CO₂H Cl H OH H SO₂ 55. OCH₂C₆H₄-2-tetrazole Cl H OH H SO₂ 56. OCH₂C₆H₄-3-tetrazole Cl H OH H SO₂ 57. OCH₂C₆H₄-3-tetrazole Cl H OH H SO₂ 58. C(NH)NH₂ H CF₃ OH H SO₂ 59. OCH₂-tetrazole H CF₃ OH H SO₂ 60. tetrazole H CF₃ OH H SO₂ 61. NHSO₂CH₃ H CF₃ OH H SO₂ 62. OCH₂CO₂Et H CF₃ OH H SO₂ 63. OCH₂CO₂H H CF₃ OH H SO₂ 64. OCH₂CH═CHCO₂Et H CF₃ OH H SO₂ 65. OCH₂CH═CHCO₂H H CF₃ OH H SO₂ 66. NHCOCH₂CO₂Et H CF₃ OH H SO₂ 67. NHCOCH₂CO₂H H CF₃ OH H SO₂ 68. OCH₂C₆H₄-2-CO₂Et H CF₃ OH H SO₂ 69. OCH₂C₆H₄-3-CO₂Et H CF₃ OH H SO₂ 70. OCH₂C₆H₄-4-CO₂Et H CF₃ OH H SO₂ 71. OCH₂C₆H₄-2-CO₂H H CF₃ OH H SO₂ 72. OCH₂C₆H₄-3-CO₂H H CF₃ OH H SO₂ 73. OCH₂C₆H₄-4-CO₂H H CF₃ OH H SO₂ 74. OCH₂C₆H₄-2-tetrazole H CF₃ OH H SO₂ 75. OCH₂C₆H₄-3-tetrazole H CF₃ OH H SO₂ 76. OCH₂C₆H₄-4-tetrazole H CF₃ OH H SO₂ 77. OCH₂-tetrazole Cl H H CH₃ SO₂ 78. tetrazole Cl H H CH₃ SO₂ 79. NHSO₂CH₃ Cl H H CH₃ SO₂ 80. OCH₂CO₂Et Cl H H CH₃ SO₂ 81. OCH₂CO₂H Cl H H CH₃ SO₂ 82. OCH₂CH═CHCO₂Et Cl H H CH₃ SO₂ 83. OCH₂CH═CHCO₂H Cl H H CH₃ SO₂ 84. NHCOCH₂CO₂Et Cl H H CH₃ SO₂ 85. NHCOCH₂CO₂H Cl H H CH₃ SO₂ 86. OCH₂C₆H₄-2-CO₂Et Cl H H CH₃ SO₂ 87. OCH₂C₆H₄-3-CO₂Et Cl H H CH₃ SO₂ 88. OCH₂C₆H₄-4-CO₂Et Cl H H CH₃ SO₂ 89. OCH₂C₆H₄-2-CO₂H Cl H H CH₃ SO₂ 90. OCH₂C₆H₄-3-CO₂H Cl H H CH₃ SO₂ 91. OCH₂C₆H₄-4-CO₂H Cl H H CH₃ SO₂ 92. OCH₂C₆H₄-2-tetrazole Cl H H CH₃ SO₂ 93. OCH₂C₆H₄-3-tetrazole Cl H H CH₃ SO₂ 94. OCH₂C₆H₄-4-tetrazole Cl H H CH₃ SO₂ 95. OCH₂-tetrazole H CF₃ H CH₃ SO₂ 96. tetrazole H CF₃ H CH₃ SO₂ 97. NHSO₂CH₃ H CF₃ H CH₃ SO₂ 98. OCH₂CO₂Et H CF₃ H CH₃ SO₂ 99. OCH₂CO₂H H CF₃ H CH₃ SO₂ 100. OCH₂CH═CHCO₂Et H CF₃ H CH₃ SO₂ 101. OCH₂CH═CHCO₂H H CF₃ H CH₃ SO₂ 102. NHCOCH₂CO₂Et H CF₃ H CH₃ SO₂ 103. NHCOCH₂CO₂H H CF₃ H CH₃ SO₂ 104. OCH₂C₆H₄-2-CO₂Et H CF₃ H CH₃ SO₂ 105. OCH₂C₆H₄-3-CO₂Et H CF₃ H CH₃ SO₂ 106. OCH₂C₆H₄-4-CO₂Et H CF₃ H CH₃ SO₂ 107. OCH₂C₆H₄-2-CO₂H H CF₃ H CH₃ SO₂ 108. OCH₂C₆H₄-3-CO₂H H CF₃ H CH₃ SO₂ 109. OCH₂C₆H₄-4-CO₂H H CF₃ H CH₃ SO₂ 110. OCH₂C₆H₄-2-tetrazole H CF₃ H CH₃ SO₂ 111. OCH₂C₆H₄-3-tetrazole H CF₃ H CH₃ SO₂ 112. OCH₂C₆H₄-4-tetrazole H CF₃ H CH₃ SO₂ 113. OCH₂-tetrazole Cl H OH CH₃ SO₂ 114. tetrazole Cl H OH CH₃ SO₂ 115. NHSO₂CH₃ Cl H OH CH₃ SO₂ 116. OCH₂CO₂Et Cl H OH CH₃ SO₂ 117. OCH₂CO₂H Cl H OH CH₃ SO₂ 118. OCH₂CH═CHCO₂Et Cl H OH CH₃ SO₂ 119. OCH₂CH═CHCO₂H Cl H OH CH₃ SO₂ 120. NHCOCH₂CO₂Et Cl H OH CH₃ SO₂ 121. NHCOCH₂CO₂H Cl H OH CH₃ SO₂ 122. OCH₂C₆H₄-2-CO₂Et Cl H OH CH₃ SO₂ 123. OCH₂C₆H₄-3-CO₂Et Cl H OH CH₃ SO₂ 124. OCH₂C₆H₄-4-CO₂Et Cl H OH CH₃ SO₂ 125. OCH₂C₆H₄-2-CO₂H Cl H OH CH₃ SO₂ 126. OCH₂C₆H₄-3-CO₂H Cl H OH CH₃ SO₂ 127. OCH₂C₆H₄-4-CO₂H Cl H OH CH₃ SO₂ 128. OCH₂C₆H₄-2-tetrazole Cl H OH CH₃ SO₂ 129. OCH₂C₆H₄-3-tetrazole Cl H OH CH₃ SO₂ 130. OCH₂C₆H₄-4-tetrazole Cl H OH CH₃ SO₂ 131. OCH₂-tetrazole H CF₃ OH CH₃ SO₂ 132. tetrazole H CF₃ OH CH₃ SO₂ 133. NHSO₂CH₃ H CF₃ OH CH₃ SO₂ 134. OCH₂CO₂Et H CF₃ OH CH₃ SO₂ 135. OCH₂CO₂H H CF₃ OH CH₃ SO₂ 136. OCH₂CH═CHCO₂Et H CF₃ OH CH₃ SO₂ 137. OCH₂CH═CHCO₂H H CF₃ OH CH₃ SO₂ 138. NHCOCH₂CO₂Et H CF₃ OH CH₃ SO₂ 139. NHCOCH₂CO₂H H CF₃ OH CH₃ SO₂ 140. OCH₂C₆H₄-2-CO₂Et H CF₃ OH CH₃ SO₂ 141. OCH₂C₆H₄-3-CO₂Et H CF₃ OH CH₃ SO₂ 142. OCH₂C₆H₄-4-CO₂Et H CF₃ OH CH₃ SO₂ 143. OCH₂C₆H₄-2-CO₂H H CF₃ OH CH₃ SO₂ 144. OCH₂C₆H₄-3-CO₂H H CF₃ OH CH₃ SO₂ 145. OCH₂C₆H₄-4-CO₂H H CF₃ OH CH₃ SO₂ 146. OCH₂C₆H₄-2-tetrazole H CF₃ OH CH₃ SO₂ 147. OCH₂C₆H₄-3-tetrazole H CF₃ OH CH₃ SO₂ 148. OCH₂C₆H₄-4-tetrazole H CF₃ OH CH₃ SO₂ 149. C(NH)NH₂ Cl H H H CO 150. OCH₂-tetrazole Cl H H H CO 151. tetrazole Cl H H H CO 152. NHSO₂CH₃ Cl H H H CO 153. OCH₂CO₂Et Cl H H H CO 154. OCH₂CO₂H Cl H H H CO 155. OCH₂CH═CHCO₂Et Cl H H H CO 156. OCH₂CH═CHCO₂H Cl H H H CO 157. NHCOCH₂CO₂Et Cl H H H CO 158. NHCOCH₂CO₂H Cl H H H CO 159. OCH₂C₆H₄-2-CO₂Et Cl H H H CO 160. OCH₂C₆H₄-3-CO₂Et Cl H H H CO 161. OCH₂C₆H₄-4-CO₂Et Cl H H H CO 162. OCH₂C₆H₄-2-CO₂H Cl H H H CO 163. OCH₂C₆H₄-3-CO₂H Cl H H H CO 164. OCH₂C₆H₄-4-CO₂H Cl H H H CO 165. OCH₂C₆H₄-2-tetrazole Cl H H H CO 166. OCH₂C₆H₄-3-tetrazole Cl H H H CO 167. OCH₂C₆H₄-4-tetrazole Cl H H H CO 168. C(NH)NH₂ H CF₃ H H CO 169. OCH₂-tetrazole H CF₃ H H CO 170. tetrazole H CF₃ H H CO 171. NHSO₂CH₃ H CF₃ H H CO 172. OCH₂CO₂Et H CF₃ H H CO 173. OCH₂CO₂H H CF₃ H H CO 174. OCH₂CH═CHCO₂Et H CF₃ H H CO 175. OCH₂CH═CHCO₂H H CF₃ H H CO 176. NHCOCH₂CO₂Et H CF₃ H H CO 177. NHCOCH₂CO₂H H CF₃ H H CO 178. OCH₂C₆H₄-2-CO₂Et H CF₃ H H CO 179. OCH₂C₆H₄-3-CO₂Et H CF₃ H H CO 180. OCH₂C₆H₄-4-CO₂Et H CF₃ H H CO 181. OCH₂C₆H₄-2-CO₂H H CF₃ H H CO 182. OCH₂C₆H₄-3-CO₂H H CF₃ H H CO 183. OCH₂C₆H₄-4-CO₂H H CF₃ H H CO 184. OCH₂C₆H₄-2-tetrazole H CF₃ H H CO 185. OCH₂C₆H₄-3-tetrazole H CF₃ H H CO 186. OCH₂C₆H₄-4-tetrazole H CF₃ H H CO 187. C(NH)NH₂ Cl H OH H CO 188. OCH₂-tetrazole Cl H OH H CO 189. tetrazole Cl H OH H CO 190. NHSO₂CH₃ Cl H OH H CO 191. OCH₂CO₂Et Cl H OH H CO 192. OCH₂CO₂H Cl H OH H CO 193. OCH₂CH═CHCO₂Et Cl H OH H CO 194. OCH₂CH═CHCO₂H Cl H OH H CO 195. NHCOCH₂CO₂Et Cl H OH H CO 196. NHCOCH₂CO₂H Cl H OH H CO 197. OCH₂C₆H₄-2-CO₂Et Cl H OH H CO 198. OCH₂C₆H₄-3-CO₂Et Cl H OH H CO 199. OCH₂C₆H₄-4-CO₂Et Cl H OH H CO 200. OCH₂C₆H₄-2-CO₂H Cl H OH H CO 201. OCH₂C₆H₄-3-CO₂H Cl H OH H CO 202. OCH₂C₆H₄-3-CO₂H Cl H OH H CO 203. OCH₂C₆H₄-2-tetrazole Cl H OH H CO 204. OCH₂C₆H₄-3-tetrazole Cl H OH H CO 205. OCH₂C₆H₄-4-tetrazole Cl H OH H CO 206. C(NH)NH₂ H CF₃ OH H CO 207. OCH₂-tetrazole H CF₃ OH H CO 208. tetrazole H CF₃ OH H CO 209. NHSO₂CH₃ H CF₃ OH H CO 210. OCH₂CO₂Et H CF₃ OH H CO 211. OCH₂CO₂H H CF₃ OH H CO 212. OCH₂CH═CHCO₂Et H CF₃ OH H CO 213. OCH₂CH═CHCO₂H H CF₃ OH H CO 214. NHCOCH₂CO₂Et H CF₃ OH H CO 215. NHCOCH₂CO₂H H CF₃ OH H CO 216. OCH₂C₆H₄-2-CO₂Et H CF₃ OH H CO 217. OCH₂C₆H₄-3-CO₂Et H CF₃ OH H CO 218. OCH₂C₆H₄-4-CO₂Et H CF₃ OH H CO 219. OCH₂C₆H₄-2-CO₂H H CF₃ OH H CO 220. OCH₂C₆H₄-3-CO₂H H CF₃ OH H CO 221. OCH₂C₆H₄-4-CO₂H H CF₃ OH H CO 222. OCH₂C₆H₄-2-tetrazole H CF₃ OH H CO 223. OCH₂C₆H₄-3-tetrazole H CF₃ OH H CO 224. OCH₂C₆H₄-4-tetrazole H CF₃ OH H CO 225. OCH₂-tetrazole Cl H H CH₃ CO 226. tetrazole Cl H H CH₃ CO 227. NHSO₂CH₃ Cl H H CH₃ CO 228. OCH₂CO₂Et Cl H H CH₃ CO 229. OCH₂CO₂H Cl H H CH₃ CO 230. OCH₂CH═CHCO₂Et Cl H H CH₃ CO 231. OCH₂CH═CHCO₂H Cl H H CH₃ CO 232. NHCOCH₂CO₂Et Cl H H CH₃ CO 233. NHCOCH₂CO₂H Cl H H CH₃ CO 234. OCH₂C₆H₄-2-CO₂Et Cl H H CH₃ CO 235. OCH₂C₆H₄-3-CO₂Et Cl H H CH₃ CO 236. OCH₂C₆H₄-4-CO₂Et Cl H H CH₃ CO 237. OCH₂C₆H₄-2-CO₂H Cl H H CH₃ CO 238. OCH₂C₆H₄-3-CO₂H Cl H H CH₃ CO 239. OCH₂C₆H₄-4-CO₂H Cl H H CH₃ CO 240. OCH₂C₆H₄-2-tetrazole Cl H H CH₃ CO 241. OCH₂C₆H₄-3-tetrazole Cl H H CH₃ CO 242. OCH₂C₆H₄-4-tetrazole Cl H H CH₃ CO 243. OCH₂-tetrazole H CF₃ H CH₃ CO 244. tetrazole H CF₃ H CH₃ CO 245. NHSO₂CH₃ H CF₃ H CH₃ CO 246. OCH₂CO₂Et H CF₃ H CH₃ CO 247. OCH₂CO₂H H CF₃ H CH₃ CO 248. OCH₂CH═CHCO₂Et H CF₃ H CH₃ CO 249. OCH₂CH═CHCO₂H H CF₃ H CH₃ CO 250. NHCOCH₂CO₂Et H CF₃ H CH₃ CO 251. NHCOCH₂CO₂H H CF₃ H CH₃ CO 252. OCH₂C₆H₄-2-CO₂Et H CF₃ H CH₃ CO 253. OCH₂C₆H₄-3-CO₂Et H CF₃ H CH₃ CO 254. OCH₂C₆H₄-4-CO₂Et H CF₃ H CH₃ CO 255. OCH₂C₆H₄-2-CO₂H H CF₃ H CH₃ CO 256. OCH₂C₆H₄-3-CO₂H H CF₃ H CH₃ CO 257. OCH₂C₆H₄-4-CO₂H H CF₃ H CH₃ CO 258. OCH₂C₆H₄-2-tetrazole H CF₃ H CH₃ CO 259. OCH₂C₆H₄-3-tetrazole H CF₃ H CH₃ CO 260. OCH₂C₆H₄-4-tetrazole H CF₃ H CH₃ CO 261. OCH₂-tetrazole Cl H OH CH₃ CO 262. tetrazole Cl H OH CH₃ CO 263. NHSO₂CH₃ Cl H OH CH₃ CO 264. OCH₂CO₂Et Cl H OH CH₃ CO 265. OCH₂CO₂H Cl H OH CH₃ CO 266. OCH₂CH═CHCO₂Et Cl H OH CH₃ CO 267. OCH₂CH═CHCO₂H Cl H OH CH₃ CO 268. NHCOCH₂CO₂Et Cl H OH CH₃ CO 269. NHCOCH₂CO₂H Cl H OH CH₃ CO 270. OCH₂C₆H₄-2-CO₂Et Cl H OH CH₃ CO 271. OCH₂C₆H₄-3-CO₂Et Cl H OH CH₃ CO 272. OCH₂C₆H₄-4-CO₂Et Cl H OH CH₃ CO 273. OCH₂C₆H₄-2-CO₂H Cl H OH CH₃ CO 274. OCH₂C₆H₄-3-CO₂H Cl H OH CH₃ CO 275. OCH₂C₆H₄-4-CO₂H Cl H OH CH₃ CO 276. OCH₂C₆H₄-2-tetrazole Cl H OH CH₃ CO 277. OCH₂C₆H₄-3-tetrazole Cl H OH CH₃ CO 278. OCH₂C₆H₄-4-tetrazole Cl H OH CH₃ CO 279. OCH₂-tetrazole H CF₃ OH CH₃ CO 280. tetrazole H CF₃ OH CH₃ CO 281. NHSO₂CH₃ H CF₃ OH CH₃ CO 282. OCH₂CO₂Et H CF₃ OH CH₃ CO 283. OCH₂CO₂H H CF₃ OH CH₃ CO 284. OCH₂CH═CHCO₂Et H CF₃ OH CH₃ CO 285. OCH₂CH═CHCO₂H H CF₃ OH CH₃ CO 286. NHCOCH₂CO₂Et H CF₃ OH CH₃ CO 287. NHCOCH₂CO₂H H CF₃ OH CH₃ CO 288. OCH₂C₆H₄-2-CO₂Et H CF₃ OH CH₃ CO 289. OCH₂C₆H₄-3-CO₂Et H CF₃ OH CH₃ CO 290. OCH₂C₆H₄-4-CO₂Et H CF₃ OH CH₃ CO 291. OCH₂C₆H₄-2-CO₂H H CF₃ OH CH₃ CO 292. OCH₂C₆H₄-3-CO₂H H CF₃ OH CH₃ CO 293. OCH₂C₆H₄-4-CO₂H H CF₃ OH CH₃ CO 294. OCH₂C₆H₄-2-tetrazole H CF₃ OH CH₃ CO 295. OCH₂C₆H₄-3-tetrazole H CF₃ OH CH₃ CO 296. OCH₂C₆H₄-4-tetrazole H CF₃ OH CH₃ CO

TABLE 1b

Ex. # X X″ Y″ Z Q M 1. C(NH)NH₂ Cl H H H SO₂ 2. OCH₂-tetrazole Cl H H H SO₂ 3. tetrazole Cl H H H SO₂ 4. NHSO₂CH₃ Cl H H H SO₂ 5. OCH₂CO₂Et Cl H H H SO₂ 6. OCH₂CO₂H Cl H H H SO₂ 7. OCH₂CH═CHCO₂Et Cl H H H SO₂ 8. OCH₂CH═CHCO₂H Cl H H H SO₂ 9. NHCOCH₂CO₂Et Cl H H H SO₂ 10. NHCOCH₂CO₂H Cl H H H SO₂ 11. OCH₂C₆H₄-2-CO₂Et Cl H H H SO₂ 12. OCH₂C₆H₄-3-CO₂Et Cl H H H SO₂ 13. OCH₂C₆H₄-4-CO₂Et Cl H H H SO₂ 14. OCH₂C₆H₄-2-CO₂H Cl H H H SO₂ 15. OCH₂C₆H₄-3-CO₂H Cl H H H SO₂ 16. OCH₂C₆H₄-4-CO₂H Cl H H H SO₂ 17. OCH₂C₆H₄-2-tetrazole Cl H H H SO₂ 18. OCH₂C₆H₄-3-tetrazole Cl H H H SO₂ 19. OCH₂C₆H₄-4-tetrazole Cl H H H SO₂ 20. C(NH)NH₂ H CF₃ H H SO₂ 21. OCH₂-tetrazole H CF₃ H H SO₂ 22. tetrazole H CF₃ H H SO₂ 23. NHSO₂CH₃ H CF₃ H H SO₂ 24. OCH₂CO₂Et H CF₃ H H SO₂ 25. OCH₂CO₂H H CF₃ H H SO₂ 26. OCH₂CH═CHCO₂Et H CF₃ H H SO₂ 27. OCH₂CH═CHCO₂H H CF₃ H H SO₂ 28. NHCOCH₂CO₂Et H CF₃ H H SO₂ 29. NHCOCH₂CO₂H H CF₃ H H SO₂ 30. OCH₂C₆H₄-2-CO₂Et H CF₃ H H SO₂ 31. OCH₂C₆H₄-3-CO₂Et H CF₃ H H SO₂ 32. OCH₂C₆H₄-4-CO₂Et H CF₃ H H SO₂ 33. OCH₂C₆H₄-2-CO₂H H CF₃ H H SO₂ 34. OCH₂C₆H₄-3-CO₂H H CF₃ H H SO₂ 35. OCH₂C₆H₄-4-CO₂H H CF₃ H H SO₂ 36. OCH₂C₆H-2-tetrazole H CF₃ H H SO₂ 37. OCH₂C₆H₄-3-tetrazole H CF₃ H H SO₂ 38. OCH₂C₆H₄-4-tetrazole H CF₃ H H SO₂ 39. C(NH)NH₂ Cl H OH H SO₂ 40. OCH₂-tetrazole Cl H OH H SO₂ 41. tetrazole Cl H OH H SO₂ 42. NHSO₂CH₃ Cl H OH H SO₂ 43. OCH₂CO₂Et Cl H OH H SO₂ 44. OCH₂CO₂H Cl H OH H SO₂ 45. OCH₂CH═CHCO₂Et Cl H OH H SO₂ 46. OCH₂CH═CHCO₂H Cl H OH H SO₂ 47. NHCOCH₂CO₂Et Cl H OH H SO₂ 48. NHCOCH₂CO₂H Cl H OH H SO₂ 49. OCH₂C₆H₄-2-CO₂Et Cl H OH H SO₂ 50. OCH₂C₆H₄-3-CO₂Et Cl H OH H SO₂ 51. OCH₂C₆H₄-4-CO₂Et Cl H OH H SO₂ 52. OCH₂C₆H₄-2-CO₂H Cl H OH H SO₂ 53. OCH₂C₆H₄-3-CO₂H Cl H OH H SO₂ 54. OCH₂C₆H₄-4-CO₂H Cl H OH H SO₂ 55. OCH₂C₆H₄-2-tetrazole Cl H OH H SO₂ 56. OCH₂C₆H₄-3-tetrazole Cl H OH H SO₂ 57. OCH₂C₆H₄-3-tetrazole Cl H OH H SO₂ 58. C(NH)NH₂ H CF₃ OH H SO₂ 59. OCH₂-tetrazole H CF₃ OH H SO₂ 60. tetrazole H CF₃ OH H SO₂ 61. NHSO₂CH₃ H CF₃ OH H SO₂ 62. OCH₂CO₂Et H CF₃ OH H SO₂ 63. OCH₂CO₂H H CF₃ OH H SO₂ 64. OCH₂CH═CHCO₂Et H CF₃ OH H SO₂ 65. OCH₂CH═CHCO₂H H CF₃ OH H SO₂ 66. NHCOCH₂CO₂Et H CF₃ OH H SO₂ 67. NHCOCH₂CO₂H H CF₃ OH H SO₂ 68. OCH₂C₆H₄-2-CO₂Et H CF₃ OH H SO₂ 69. OCH₂C₆H₄-3-CO₂Et H CF₃ OH H SO₂ 70. OCH₂C₆H₄-4-CO₂Et H CF₃ OH H SO₂ 71. OCH₂C₆H₄-2-CO₂H H CF₃ OH H SO₂ 72. OCH₂C₆H₄-3-CO₂H H CF₃ OH H SO₂ 73. OCH₂C₆H₄-4-CO₂H H CF₃ OH H SO₂ 74. OCH₂C₆H₄-2-tetrazole H CF₃ OH H SO₂ 75. OCH₂C₆H₄-3-tetrazole H CF₃ OH H SO₂ 76. OCH₂C₆H₄-4-tetrazole H CF₃ OH H SO₂ 77. OCH₂-tetrazole Cl H H CH₃ SO₂ 78. tetrazole Cl H H CH₃ SO₂ 79. NHSO₂CH₃ Cl H H CH₃ SO₂ 80. OCH₂CO₂Et Cl H H CH₃ SO₂ 81. OCH₂CO₂H Cl H H CH₃ SO₂ 82. OCH₂CH═CHCO₂Et Cl H H CH₃ SO₂ 83. OCH₂CH═CHCO₂H Cl H H CH₃ SO₂ 84. NHCOCH₂CO₂Et Cl H H CH₃ SO₂ 85. NHCOCH₂CO₂H Cl H H CH₃ SO₂ 86. OCH₂C₆H₄-2-CO₂Et Cl H H CH₃ SO₂ 87. OCH₂C₆H₄-3-CO₂Et Cl H H CH₃ SO₂ 88. OCH₂C₆H₄-4-CO₂Et Cl H H CH₃ SO₂ 89. OCH₂C₆H₄-2-CO₂H Cl H H CH₃ SO₂ 90. OCH₂C₆H₄-3-CO₂H Cl H H CH₃ SO₂ 91. OCH₂C₆H₄-4-CO₂H Cl H H CH₃ SO₂ 92. OCH₂C₆H₄-2-tetrazole Cl H H CH₃ SO₂ 93. OCH₂C₆H₄-3-tetrazole Cl H H CH₃ SO₂ 94. OCH₂C₆H₄-4-tetrazole Cl H H CH₃ SO₂ 95. OCH₂-tetrazole H CF₃ H CH₃ SO₂ 96. tetrazole H CF₃ H CH₃ SO₂ 97. NHSO₂CH₃ H CF₃ H CH₃ SO₂ 98. OCH₂CO₂Et H CF₃ H CH₃ SO₂ 99. OCH₂CO₂H H CF₃ H CH₃ SO₂ 100. OCH₂CH═CHCO₂Et H CF₃ H CH₃ SO₂ 101. OCH₂CH═CHCO₂H H CF₃ H CH₃ SO₂ 102. NHCOCH₂CO₂Et H CF₃ H CH₃ SO₂ 103. NHCOCH₂CO₂H H CF₃ H CH₃ SO₂ 104. OCH₂C₆H₄-2-CO₂Et H CF₃ H CH₃ SO₂ 105. OCH₂C₆H₄-3-CO₂Et H CF₃ H CH₃ SO₂ 106. OCH₂C₆H₄-4-CO₂Et H CF₃ H CH₃ SO₂ 107. OCH₂C₆H₄-2-CO₂H H CF₃ H CH₃ SO₂ 108. OCH₂C₆H₄-3-CO₂H H CF₃ H CH₃ SO₂ 109. OCH₂C₆H₄-4-CO₂H H CF₃ H CH₃ SO₂ 110. OCH₂C₆H₄-2-tetrazole H CF₃ H CH₃ SO₂ 111. OCH₂C₆H₄-3-tetrazole H CF₃ H CH₃ SO₂ 112. OCH₂C₆H₄-4-tetrazole H CF₃ H CH₃ SO₂ 113. OCH₂-tetrazole Cl H OH CH₃ SO₂ 114. tetrazole Cl H OH CH₃ SO₂ 115. NHSO₂CH₃ Cl H OH CH₃ SO₂ 116. OCH₂CO₂Et Cl H OH CH₃ SO₂ 117. OCH₂CO₂H Cl H OH CH₃ SO₂ 118. OCH₂CH═CHCO₂Et Cl H OH CH₃ SO₂ 119. OCH₂CH═CHCO₂H Cl H OH CH₃ SO₂ 120. NHCOCH₂CO₂Et Cl H OH CH₃ SO₂ 121. NHCOCH₂CO₂H Cl H OH CH₃ SO₂ 122. OCH₂C₆H₄-2-CO₂Et Cl H OH CH₃ SO₂ 123. OCH₂C₆H₄-3-CO₂Et Cl H OH CH₃ SO₂ 124. OCH₂C₆H₄-4-CO₂Et Cl H OH CH₃ SO₂ 125. OCH₂C₆H₄-2-CO₂H Cl H OH CH₃ SO₂ 126. OCH₂C₆H₄-3-CO₂H Cl H OH CH₃ SO₂ 127. OCH₂C₆H₄-4-CO₂H Cl H OH CH₃ SO₂ 128. OCH₂C₆H₄-2-tetrazole Cl H OH CH₃ SO₂ 129. OCH₂C₆H₄-3-tetrazole Cl H OH CH₃ SO₂ 130. OCH₂C₆H₄-4-tetrazole Cl H OH CH₃ SO₂ 131. OCH₂-tetrazole H CF₃ OH CH₃ SO₂ 132. tetrazole H CF₃ OH CH₃ SO₂ 133. NHSO₂CH₃ H CF₃ OH CH₃ SO₂ 134. OCH₂CO₂Et H CF₃ OH CH₃ SO₂ 135. OCH₂CO₂H H CF₃ OH CH₃ SO₂ 136. OCH₂CH═CHCO₂Et H CF₃ OH CH₃ SO₂ 137. OCH₂CH═CHCO₂H H CF₃ OH CH₃ SO₂ 138. NHCOCH₂CO₂Et H CF₃ OH CH₃ SO₂ 139. NHCOCH₂CO₂H H CF₃ OH CH₃ SO₂ 140. OCH₂C₆H₄-2-CO₂Et H CF₃ OH CH₃ SO₂ 141. OCH₂C₆H₄-3-CO₂Et H CF₃ OH CH₃ SO₂ 142. OCH₂C₆H₄-4-CO₂Et H CF₃ OH CH₃ SO₂ 143. OCH₂C₆H₄-2-CO₂H H CF₃ OH CH₃ SO₂ 144. OCH₂C₆H₄-3-CO₂H H CF₃ OH CH₃ SO₂ 145. OCH₂C₆H₄-4-CO₂H H CF₃ OH CH₃ SO₂ 146. OCH₂C₆H₄-2-tetrazole H CF₃ OH CH₃ SO₂ 147. OCH₂C₆H₄-3-tetrazole H CF₃ OH CH₃ SO₂ 148. OCH₂C₆H₄-4-tetrazole H CF₃ OH CH₃ SO₂ 149. C(NH)NH₂ Cl H H H CO 150. OCH₂-tetrazole Cl H H H CO 151. tetrazole Cl H H H CO 152. NHSO₂CH₃ Cl H H H CO 153. OCH₂CO₂Et Cl H H H CO 154. OCH₂CO₂H Cl H H H CO 155. OCH₂CH═CHCO₂Et Cl H H H CO 156. OCH₂CH═CHCO₂H Cl H H H CO 157. NHCOCH₂CO₂Et Cl H H H CO 158. NHCOCH₂CO₂H Cl H H H CO 159. OCH₂C₆H₄-2-CO₂Et Cl H H H CO 160. OCH₂C₆H₄-3-CO₂Et Cl H H H CO 161. OCH₂C₆H₄-4-CO₂Et Cl H H H CO 162. OCH₂C₆H₄-2-CO₂H Cl H H H CO 163. OCH₂C₆H₄-3-CO₂H Cl H H H CO 164. OCH₂C₆H₄-4-CO₂H Cl H H H CO 165. OCH₂C₆H₄-2-tetrazole Cl H H H CO 166. OCH₂C₆H₄-3-tetrazole Cl H H H CO 167. OCH₂C₆H₄-4-tetrazole Cl H H H CO 168. C(NH)NH₂ H CF₃ H H CO 169. OCH₂-tetrazole H CF₃ H H CO 170. tetrazole H CF₃ H H CO 171. NHSO₂CH₃ H CF₃ H H CO 172. OCH₂CO₂Et H CF₃ H H CO 173. OCH₂CO₂H H CF₃ H H CO 174. OCH₂CH═CHCO₂Et H CF₃ H H CO 175. OCH₂CH═CHCO₂H H CF₃ H H CO 176. NHCOCH₂CO₂Et H CF₃ H H CO 177. NHCOCH₂CO₂H H CF₃ H H CO 178. OCH₂C₆H₄-2-CO₂Et H CF₃ H H CO 179. OCH₂C₆H₄-3-CO₂Et H CF₃ H H CO 180. OCH₂C₆H₄-4-CO₂Et H CF₃ H H CO 181. OCH₂C₆H₄-2-CO₂H H CF₃ H H CO 182. OCH₂C₆H₄-3-CO₂H H CF₃ H H CO 183. OCH₂C₆H₄-4-CO₂H H CF₃ H H CO 184. OCH₂C₆H₄-2-tetrazole H CF₃ H H CO 185. OCH₂C₆H₄-3-tetrazole H CF₃ H H CO 186. OCH₂C₆H₄-4-tetrazole H CF₃ H H CO 187. C(NH)NH₂ Cl H OH H CO 188. OCH₂-tetrazole Cl H OH H CO 189. tetrazole Cl H OH H CO 190. NHSO₂CH₃ Cl H OH H CO 191. OCH₂CO₂Et Cl H OH H CO 192. OCH₂CO₂H Cl H OH H CO 193. OCH₂CH═CHCO₂Et Cl H OH H CO 194. OCH₂CH═CHCO₂H Cl H OH H CO 195. NHCOCH₂CO₂Et Cl H OH H CO 196. NHCOCH₂CO₂H Cl H OH H CO 197. OCH₂C₆H₄-2-CO₂Et Cl H OH H CO 198. OCH₂C₆H₄-3-CO₂Et Cl H OH H CO 199. OCH₂C₆H₄-4-CO₂Et Cl H OH H CO 200. OCH₂C₆H₄-2-CO₂H Cl H OH H CO 201. OCH₂C₆H₄-3-CO₂H Cl H OH H CO 202. OCH₂C₆H₄-3-CO₂H Cl H OH H CO 203. OCH₂C₆H₄-2-tetrazole Cl H OH H CO 204. OCH₂C₆H₄-3-tetrazole Cl H OH H CO 205. OCH₂C₆H₄-4-tetrazole Cl H OH H CO 206. C(NH)NH₂ H CF₃ OH H CO 207. OCH₂-tetrazole H CF₃ OH H CO 208. tetrazole H CF₃ OH H CO 209. NHSO₂CH₃ H CF₃ OH H CO 210. OCH₂CO₂Et H CF₃ OH H CO 211. OCH₂CO₂H H CF₃ OH H CO 212. OCH₂CH═CHCO₂Et H CF₃ OH H CO 213. OCH₂CH═CHCO₂H H CF₃ OH H CO 214. NHCOCH₂CO₂Et H CF₃ OH H CO 215. NHCOCH₂CO₂H H CF₃ OH H CO 216. OCH₂C₆H₄-2-CO₂Et H CF₃ OH H CO 217. OCH₂C₆H₄-3-CO₂Et H CF₃ OH H CO 218. OCH₂C₆H₄-4-CO₂Et H CF₃ OH H CO 219. OCH₂C₆H₄-2-CO₂H H CF₃ OH H CO 220. OCH₂C₆H₄-3-CO₂H H CF₃ OH H CO 221. OCH₂C₆H₄-4-CO₂H H CF₃ OH H CO 222. OCH₂C₆H₄-2-tetrazole H CF₃ OH H CO 223. OCH₂C₆H₄-3-tetrazole H CF₃ OH H CO 224. OCH₂C₆H₄-4-tetrazole H CF₃ OH H CO 225. OCH₂-tetrazole Cl H H CH₃ CO 226. tetrazole Cl H H CH₃ CO 227. NHSO₂CH₃ Cl H H CH₃ CO 228. OCH₂CO₂Et Cl H H CH₃ CO 229. OCH₂CO₂H Cl H H CH₃ CO 230. OCH₂CH═CHCO₂Et Cl H H CH₃ CO 231. OCH₂CH═CHCO₂H Cl H H CH₃ CO 232. NHCOCH₂CO₂Et Cl H H CH₃ CO 233. NHCOCH₂CO₂H Cl H H CH₃ CO 234. OCH₂C₆H₄-2-CO₂Et Cl H H CH₃ CO 235. OCH₂C₆H₄-3-CO₂Et Cl H H CH₃ CO 236. OCH₂C₆H₄-4-CO₂Et Cl H H CH₃ CO 237. OCH₂C₆H₄-2-CO₂H Cl H H CH₃ CO 238. OCH₂C₆H₄-3-CO₂H Cl H H CH₃ CO 239. OCH₂C₆H₄-4-CO₂H Cl H H CH₃ CO 240. OCH₂C₆H₄-2-tetrazole Cl H H CH₃ CO 241. OCH₂C₆H₄-3-tetrazole Cl H H CH₃ CO 242. OCH₂C₆H₄-4-tetrazole Cl H H CH₃ CO 243. OCH₂-tetrazole H CF₃ H CH₃ CO 244. tetrazole H CF₃ H CH₃ CO 245. NHSO₂CH₃ H CF₃ H CH₃ CO 246. OCH₂CO₂Et H CF₃ H CH₃ CO 247. OCH₂CO₂H H CF₃ H CH₃ CO 248. OCH₂CH═CHCO₂Et H CF₃ H CH₃ CO 249. OCH₂CH═CHCO₂H H CF₃ H CH₃ CO 250. NHCOCH₂CO₂Et H CF₃ H CH₃ CO 251. NHCOCH₂CO₂H H CF₃ H CH₃ CO 252. OCH₂C₆H₄-2-CO₂Et H CF₃ H CH₃ CO 253. OCH₂C₆H₄-3-CO₂Et H CF₃ H CH₃ CO 254. OCH₂C₆H₄-4-CO₂Et H CF₃ H CH₃ CO 255. OCH₂C₆H₄-2-CO₂H H CF₃ H CH₃ CO 256. OCH₂C₆H₄-3-CO₂H H CF₃ H CH₃ CO 257. OCH₂C₆H₄-4-CO₂H H CF₃ H CH₃ CO 258. OCH₂C₆H₄-2-tetrazole H CF₃ H CH₃ CO 259. OCH₂C₆H₄-3-tetrazole H CF₃ H CH₃ CO 260. OCH₂C₆H₄-4-tetrazole H CF₃ H CH₃ CO 261. OCH₂-tetrazole Cl H OH CH₃ CO 262. tetrazole Cl H OH CH₃ CO 263. NHSO₂CH₃ Cl H OH CH₃ CO 264. OCH₂CO₂Et Cl H OH CH₃ CO 265. OCH₂CO₂H Cl H OH CH₃ CO 266. OCH₂CH═CHCO₂Et Cl H OH CH₃ CO 267. OCH₂CH═CHCO₂H Cl H OH CH₃ CO 268. NHCOCH₂CO₂Et Cl H OH CH₃ CO 269. NHCOCH₂CO₂H Cl H OH CH₃ CO 270. OCH₂C₆H₄-2-CO₂Et Cl H OH CH₃ CO 271. OCH₂C₆H₄-3-CO₂Et Cl H OH CH₃ CO 272. OCH₂C₆H₄-4-CO₂Et Cl H OH CH₃ CO 273. OCH₂C₆H₄-2-CO₂H Cl H OH CH₃ CO 274. OCH₂C₆H₄-3-CO₂H Cl H OH CH₃ CO 275. OCH₂C₆H₄-4-CO₂H Cl H OH CH₃ CO 276. OCH₂C₆H₄-2-tetrazole Cl H OH CH₃ CO 277. OCH₂C₆H₄-3-tetrazole Cl H OH CH₃ CO 278. OCH₂C₆H₄-4-tetrazole Cl H OH CH₃ CO 279. OCH₂-tetrazole H CF₃ OH CH₃ CO 280. tetrazole H CF₃ OH CH₃ CO 281. NHSO₂CH₃ H CF₃ OH CH₃ CO 282. OCH₂CO₂Et H CF₃ OH CH₃ CO 283. OCH₂CO₂H H CF₃ OH CH₃ CO 284. OCH₂CH═CHCO₂Et H CF₃ OH CH₃ CO 285. OCH₂CH═CHCO₂H H CF₃ OH CH₃ CO 286. NHCOCH₂CO₂Et H CF₃ OH CH₃ CO 287. NHCOCH₂CO₂H H CF₃ OH CH₃ CO 288. OCH₂C₆H₄-2-CO₂Et H CF₃ OH CH₃ CO 289. OCH₂C₆H₄-3-CO₂Et H CF₃ OH CH₃ CO 290. OCH₂C₆H₄-4-CO₂Et H CF₃ OH CH₃ CO 291. OCH₂C₆H₄-2-CO₂H H CF₃ OH CH₃ CO 292. OCH₂C₆H₄-3-CO₂H H CF₃ OH CH₃ CO 293. OCH₂C₆H₄-4-CO₂H H CF₃ OH CH₃ CO 294. OCH₂C₆H₄-2-tetrazole H CF₃ OH CH₃ CO 295. OCH₂C₆H₄-3-tetrazole H CF₃ OH CH₃ CO 296. OCH₂C₆H₄-4-tetrazole H CF₃ OH CH₃ CO

TABLE 1c

Ex. # X″ Z Q M 1. C(NH)NH₂ H H SO₂ 2. OCH₂-tetrazole H H SO₂ 3. tetrazole H H SO₂ 4. NHSO₂CH₃ H H SO₂ 5. OCH₂CO₂Et H H SO₂ 6. OCH₂CO₂H H H SO₂ 7. OCH₂CH═CHCO₂Et H H SO₂ 8. OCH₂CH═CHCO₂H H H SO₂ 9. NHCOCH₂CO₂Et H H SO₂ 10. NHCOCH₂CO₂H H H SO₂ 11. OCH₂C₆H₄-2-CO₂Et H H SO₂ 12. OCH₂C₆H₄-3-CO₂Et H H SO₂ 13. OCH₂C₆H₄-4-CO₂Et H H SO₂ 14. OCH₂C₆H₄-2-CO₂H H H SO₂ 15. OCH₂C₆H₄-3-CO₂H H H SO₂ 16. OCH₂C₆H₄-4-CO₂H H H SO₂ 17. OCH₂C₆H₄-2-tetrazole H H SO₂ 18. OCH₂C₆H₄-3-tetrazole H H SO₂ 19. OCH₂C₆H₄-4-tetrazole H H SO₂ 20. C(NH)NH₂ OH H SO₂ 21. OCH₂-tetrazole OH H SO₂ 22. tetrazole OH H SO₂ 23. NHSO₂CH₃ OH H SO₂ 24. OCH₂CO₂Et OH H SO₂ 25. OCH₂CO₂H OH H SO₂ 26. OCH₂CH═CHCO₂Et OH H SO₂ 27. OCH₂CH═CHCO₂H OH H SO₂ 28. NHCOCH₂CO₂Et OH H SO₂ 29. NHCOCH₂CO₂H OH H SO₂ 30. OCH₂C₆H₄-2-CO₂Et OH H SO₂ 31. OCH₂C₆H₄-3-CO₂Et OH H SO₂ 32. OCH₂C₆H₄-4-CO₂Et OH H SO₂ 33. OCH₂C₆H₄-2-CO₂H OH H SO₂ 34. OCH₂C₆H₄-3-CO₂H OH H SO₂ 35. OCH₂C₆H₄-4-CO₂H OH H SO₂ 36. OCH₂C₆H₄-2-tetrazole OH H SO₂ 37. OCH₂C₆H₄-3-tetrazole OH H SO₂ 38. OCH₂C₆H₄-4-tetrazole OH H SO₂ 39. OCH₂-tetrazole H CH₃ SO₂ 40. tetrazole H CH₃ SO₂ 41. NHSO₂CH₃ H CH₃ SO₂ 42. OCH₂CO₂Et H CH₃ SO₂ 43. OCH₂CO₂H H CH₃ SO₂ 44. OCH₂CH═CHCO₂Et H CH₃ SO₂ 45. OCH₂CH═CHCO₂H H CH₃ SO₂ 46. NHCOCH₂CO₂Et H CH₃ SO₂ 47. NHCOCH₂CO₂H H CH₃ SO₂ 48. OCH₂C₆H₄-2-CO₂Et H CH₃ SO₂ 49. OCH₂C₆H₄-3-CO₂Et H CH₃ SO₂ 50. OCH₂C₆H₄-4-CO₂Et H CH₃ SO₂ 51. OCH₂C₆H₄-2-CO₂H H CH₃ SO₂ 52. OCH₂C₆H₄-3-CO₂H H CH₃ SO₂ 53. OCH₂C₆H₄-4-CO₂H H CH₃ SO₂ 54. OCH₂C₆H₄-2-tetrazole H CH₃ SO₂ 55. OCH₂C₆H₄-3-tetrazole H CH₃ SO₂ 56. OCH₂C₆H₄-4-tetrazole H CH₃ SO₂ 57. OCH₂-tetrazole OH CH₃ SO₂ 58. tetrazole OH CH₃ SO₂ 59. NHSO₂CH₃ OH CH₃ SO₂ 60. OCH₂CO₂Et OH CH₃ SO₂ 61. OCH₂CO₂H OH CH₃ SO₂ 62. OCH₂CH═CHCO₂Et OH CH₃ SO₂ 63. OCH₂CH═CHCO₂H OH CH₃ SO₂ 64. NHCOCH₂CO₂Et OH CH₃ SO₂ 65. NHCOCH₂CO₂H OH CH₃ SO₂ 66. OCH₂C₆H₄-2-CO₂Et OH CH₃ SO₂ 67. OCH₂C₆H₄-3-CO₂Et OH CH₃ SO₂ 68. OCH₂C₆H₄-4-CO₂Et OH CH₃ SO₂ 69. OCH₂C₆H₄-2-CO₂H OH CH₃ SO₂ 70. OCH₂C₆H₄-3-CO₂H OH CH₃ SO₂ 71. OCH₂C₆H₄-4-CO₂H OH CH₃ SO₂ 72. OCH₂C₆H₄-2-tetrazole OH CH₃ SO₂ 73. OCH₂C₆H₄-3-tetrazole OH CH₃ SO₂ 74. OCH₂C₆H₄-4-tetrazole OH CH₃ SO₂ 75. C(NH)NH₂ H H CO 76. OCH₂-tetrazole H H CO 77. tetrazole H H CO 78. NHSO₂CH₃ H H CO 79. OCH₂CO₂Et H H CO 80. OCH₂CO₂H H H CO 81. OCH₂CH═CHCO₂Et H H CO 82. OCH₂CH═CHCO₂H H H CO 83. NHCOCH₂CO₂Et H H CO 84. NHCOCH₂CO₂H H H CO 85. OCH₂C₆H₄-2-CO₂Et H H CO 86. OCH₂C₆H₄-3-CO₂Et H H CO 87. OCH₂C₆H₄-4-CO₂Et H H CO 88. OCH₂C₆H₄-2-CO₂H H H CO 89. OCH₂C₆H₄-3-CO₂H H H CO 90. OCH₂C₆H₄-4-CO₂H H H CO 91. OCH₂C₆H₄-2-tetrazole H H CO 92. OCH₂C₆H₄-3-tetrazole H H CO 93. OCH₂C₆H₄-4-tetrazole H H CO 94. C(NH)NH₂ OH H CO 95. OCH₂-tetrazole OH H CO 96. tetrazole OH H CO 97. NHSO₂CH₃ OH H CO 98. OCH₂CO₂Et OH H CO 99. OCH₂CO₂H OH H CO 100. OCH₂CH═CHCO₂Et OH H CO 101. OCH₂CH═CHCO₂H OH H CO 102. NHCOCH₂CO₂Et OH H CO 103. NHCOCH₂CO₂H OH H CO 104. OCH₂C₆H₄-2-CO₂Et OH H CO 105. OCH₂C₆H₄-3-CO₂Et OH H CO 106. OCH₂C₆H₄-4-CO₂Et OH H CO 107. OCH₂C₆H₄-2-CO₂H OH H CO 108. OCH₂C₆H₄-3-CO₂H OH H CO 109. OCH₂C₆H₄-4-CO₂H OH H CO 110. OCH₂C₆H₄-2-tetrazole OH H CO 111. OCH₂C₆H₄-3-tetrazole OH H CO 112. OCH₂C₆H₄-4-tetrazole OH H CO 113. OCH₂-tetrazole H CH₃ CO 114. tetrazole H CH₃ CO 115. NHSO₂CH₃ H CH₃ CO 116. OCH₂CO₂Et H CH₃ CO 117. OCH₂CO₂H H CH₃ CO 118. OCH₂CH═CHCO₂Et H CH₃ CO 119. OCH₂CH═CHCO₂H H CH₃ CO 120. NHCOCH₂CO₂Et H CH₃ CO 121. NHCOCH₂CO₂H H CH₃ CO 122. OCH₂C₆H₄-2-CO₂Et H CH₃ CO 123. OCH₂C₆H₄-3-CO₂Et H CH₃ CO 124. OCH₂C₆H₄-4-CO₂Et H CH₃ CO 125. OCH₂C₆H₄-2-CO₂H H CH₃ CO 126. OCH₂C₆H₄-3-CO₂H H CH₃ CO 127. OCH₂C₆H₄-4-CO₂H H CH₃ CO 128. OCH₂C₆H₄-2-tetrazole H CH₃ CO 129. OCH₂C₆H₄-3-tetrazole H CH₃ CO 130. OCH₂C₆H₄-4-tetrazole H CH₃ CO 131. OCH₂-tetrazole OH CH₃ CO 132. tetrazole OH CH₃ CO 133. NHSO₂CH₃ OH CH₃ CO 134. OCH₂CO₂Et OH CH₃ CO 135. OCH₂CO₂H OH CH₃ CO 136. OCH₂CH═CHCO₂Et OH CH₃ CO 137. OCH₂CH═CHCO₂H OH CH₃ CO 138. NHCOCH₂CO₂Et OH CH₃ CO 139. NHCOCH₂CO₂H OH CH₃ CO 140. OCH₂C₆H₄-2-CO₂Et OH CH₃ CO 141. OCH₂C₆H₄-3-CO₂Et OH CH₃ CO 142. OCH₂C₆H₄-4-CO₂Et OH CH₃ CO 143. OCH₂C₆H₄-2-CO₂H OH CH₃ CO 144. OCH₂C₆H₄-3-CO₂H OH CH₃ CO 145. OCH₂C₆H₄-4-CO₂H OH CH₃ CO 146. OCH₂C₆H₄-2-tetrazole OH CH₃ CO 147. OCH₂C₆H₄-3-tetrazole OH CH₃ CO 148. OCH₂C₆H₄-4-tetrazole OH CH₃ CO

TABLE 1d

Ex. # Y″ Z Q M 1. C(NH)NH₂ H H SO₂ 2. OCH₂-tetrazole H H SO₂ 3. tetrazole H H SO₂ 4. NHSO₂CH₃ H H SO₂ 5. OCH₂CO₂Et H H SO₂ 6. OCH₂CO₂H H H SO₂ 7. OCH₂CH═CHCO₂Et H H SO₂ 8. OCH₂CH═CHCO₂H H H SO₂ 9. NHCOCH₂CO₂Et H H SO₂ 10. NHCOCH₂CO₂H H H SO₂ 11. OCH₂C₆H₄-2-CO₂Et H H SO₂ 12. OCH₂C₆H₄-3-CO₂Et H H SO₂ 13. OCH₂C₆H₄-4-CO₂Et H H SO₂ 14. OCH₂C₆H₄-2-CO₂H H H SO₂ 15. OCH₂C₆H₄-3-CO₂H H H SO₂ 16. OCH₂C₆H₄-4-CO₂H H H SO₂ 17. OCH₂C₆H₄-2-tetrazole H H SO₂ 18. OCH₂C₆H₄-3-tetrazole H H SO₂ 19. OCH₂C₆H₄-4-tetrazole H H SO₂ 20. C(NH)NH₂ OH H SO₂ 21. OCH₂-tetrazole OH H SO₂ 22. tetrazole OH H SO₂ 23. NHSO₂CH₃ OH H SO₂ 24. OCH₂CO₂Et OH H SO₂ 25. OCH₂CO₂H OH H SO₂ 26. OCH₂CH═CHCO₂Et OH H SO₂ 27. OCH₂CH═CHCO₂H OH H SO₂ 28. NHCOCH₂CO₂Et OH H SO₂ 29. NHCOCH₂CO₂H OH H SO₂ 30. OCH₂C₆H₄-2-CO₂Et OH H SO₂ 31. OCH₂C₆H₄-3-CO₂Et OH H SO₂ 32. OCH₂C₆H₄-4-CO₂Et OH H SO₂ 33. OCH₂C₆H₄-2-CO₂H OH H SO₂ 34. OCH₂C₆H₄-3-CO₂H OH H SO₂ 35. OCH₂C₆H₄-4-CO₂H OH H SO₂ 36. OCH₂C₆H₄-2-tetrazole OH H SO₂ 37. OCH₂C₆H₄-3-tetrazole OH H SO₂ 38. OCH₂C₆H₄-4-tetrazole OH H SO₂ 39. OCH₂-tetrazole H CH₃ SO₂ 40. tetrazole H CH₃ SO₂ 41. NHSO₂CH₃ H CH₃ SO₂ 42. OCH₂CO₂Et H CH₃ SO₂ 43. OCH₂CO₂H H CH₃ SO₂ 44. OCH₂CH═CHCO₂Et H CH₃ SO₂ 45. OCH₂CH═CHCO₂H H CH₃ SO₂ 46. NHCOCH₂CO₂Et H CH₃ SO₂ 47. NHCOCH₂CO₂H H CH₃ SO₂ 48. OCH₂C₆H₄-2-CO₂Et H CH₃ SO₂ 49. OCH₂C₆H₄-3-CO₂Et H CH₃ SO₂ 50. OCH₂C₆H₄-4-CO₂Et H CH₃ SO₂ 51. OCH₂C₆H₄-2-CO₂H H CH₃ SO₂ 52. OCH₂C₆H₄-3-CO₂H H CH₃ SO₂ 53. OCH₂C₆H₄-4-CO₂H H CH₃ SO₂ 54. OCH₂C₆H₄-2-tetrazole H CH₃ SO₂ 55. OCH₂C₆H₄-3-tetrazole H CH₃ SO₂ 56. OCH₂C₆H₄-4-tetrazole H CH₃ SO₂ 57. OCH₂-tetrazole OH CH₃ SO₂ 58. tetrazole OH CH₃ SO₂ 59. NHSO₂CH₃ OH CH₃ SO₂ 60. OCH₂CO₂Et OH CH₃ SO₂ 61. OCH₂CO₂H OH CH₃ SO₂ 62. OCH₂CH═CHCO₂Et OH CH₃ SO₂ 63. OCH₂CH═CHCO₂H OH CH₃ SO₂ 64. NHCOCH₂CO₂Et OH CH₃ SO₂ 65. NHCOCH₂CO₂H OH CH₃ SO₂ 66. OCH₂C₆H₄-2-CO₂Et OH CH₃ SO₂ 67. OCH₂C₆H₄-3-CO₂Et OH CH₃ SO₂ 68. OCH₂C₆H₄-4-CO₂Et OH CH₃ SO₂ 69. OCH₂C₆H₄-2-CO₂H OH CH₃ SO₂ 70. OCH₂C₆H₄-3-CO₂H OH CH₃ SO₂ 71. OCH₂C₆H₄-4-CO₂H OH CH₃ SO₂ 72. OCH₂C₆H₄-2-tetrazole OH CH₃ SO₂ 73. OCH₂C₆H₄-3-tetrazole OH CH₃ SO₂ 74. OCH₂C₆H₄-4-tetrazole OH CH₃ SO₂ 75. C(NH)NH₂ H H CO 76. OCH₂-tetrazole H H CO 77. tetrazole H H CO 78. NHSO₂CH₃ H H CO 79. OCH₂CO₂Et H H CO 80. OCH₂CO₂H H H CO 81. OCH₂CH═CHCO₂Et H H CO 82. OCH₂CH═CHCO₂H H H CO 83. NHCOCH₂CO₂Et H H CO 84. NHCOCH₂CO₂H H H CO 85. OCH₂C₆H₄-2-CO₂Et H H CO 86. OCH₂C₆H₄-3-CO₂Et H H CO 87. OCH₂C₆H₄-4-CO₂Et H H CO 88. OCH₂C₆H₄-2-CO₂H H H CO 89. OCH₂C₆H₄-3-CO₂H H H CO 90. OCH₂C₆H₄-4-CO₂H H H CO 91. OCH₂C₆H₄-2-tetrazole H H CO 92. OCH₂C₆H₄-3-tetrazole H H CO 93. OCH₂C₆H₄-4-tetrazole H H CO 94. C(NH)NH₂ OH H CO 95. OCH₂-tetrazole OH H CO 96. tetrazole OH H CO 97. NHSO₂CH₃ OH H CO 98. OCH₂CO₂Et OH H CO 99. OCH₂CO₂H OH H CO 100. OCH₂CH═CHCO₂Et OH H CO 101. OCH₂CH═CHCO₂H OH H CO 102. NHCOCH₂CO₂Et OH H CO 103. NHCOCH₂CO₂H OH H CO 104. OCH₂C₆H₄-2-CO₂Et OH H CO 105. OCH₂C₆H₄-3-CO₂Et OH H CO 106. OCH₂C₆H₄-4-CO₂Et OH H CO 107. OCH₂C₆H₄-2-CO₂H OH H CO 108. OCH₂C₆H₄-3-CO₂H OH H CO 109. OCH₂C₆H₄-4-CO₂H OH H CO 110. OCH₂C₆H₄-2-tetrazole OH H CO 111. OCH₂C₆H₄-3-tetrazole OH H CO 112. OCH₂C₆H₄-4-tetrazole OH H CO 113. OCH₂-tetrazole H CH₃ CO 114. tetrazole H CH₃ CO 115. NHSO₂CH₃ H CH₃ CO 116. OCH₂CO₂Et H CH₃ CO 117. OCH₂CO₂H H CH₃ CO 118. OCH₂CH═CHCO₂Et H CH₃ CO 119. OCH₂CH═CHCO₂H H CH₃ CO 120. NHCOCH₂CO₂Et H CH₃ CO 121. NHCOCH₂CO₂H H CH₃ CO 122. OCH₂C₆H₄-2-CO₂Et H CH₃ CO 123. OCH₂C₆H₄-3-CO₂Et H CH₃ CO 124. OCH₂C₆H₄-4-CO₂Et H CH₃ CO 125. OCH₂C₆H₄-2-CO₂H H CH₃ CO 126. OCH₂C₆H₄-3-CO₂H H CH₃ CO 127. OCH₂C₆H₄-4-CO₂H H CH₃ CO 128. OCH₂C₆H₄-2-tetrazole H CH₃ CO 129. OCH₂C₆H₄-3-tetrazole H CH₃ CO 130. OCH₂C₆H₄-4-tetrazole H CH₃ CO 131. OCH₂-tetrazole OH CH₃ CO 132. tetrazole OH CH₃ CO 133. NHSO₂CH₃ OH CH₃ CO 134. OCH₂CO₂Et OH CH₃ CO 135. OCH₂CO₂H OH CH₃ CO 136. OCH₂CH═CHCO₂Et OH CH₃ CO 137. OCH₂CH═CHCO₂H OH CH₃ CO 138. NHCOCH₂CO₂Et OH CH₃ CO 139. NHCOCH₂CO₂H OH CH₃ CO 140. OCH₂C₆H₄-2-CO₂Et OH CH₃ CO 141. OCH₂C₆H₄-3-CO₂Et OH CH₃ CO 142. OCH₂C₆H₄-4-CO₂Et OH CH₃ CO 143. OCH₂C₆H₄-2-CO₂H OH CH₃ CO 144. OCH₂C₆H₄-3-CO₂H OH CH₃ CO 145. OCH₂C₆H₄-4-CO₂H OH CH₃ CO 146. OCH₂C₆H₄-2-tetrazole OH CH₃ CO 147. OCH₂C₆H₄-3-tetrazole OH CH₃ CO 148. OCH₂C₆H₄-4-tetrazole OH CH₃ CO

TABLE 2

Ex. # X X″ Y″ Z Q M 1. H Cl H H CH₂CO₂Et SO₂ 2. H Cl H H CH₂CO₂H SO₂ 3. Cl Cl H H CH₂CO₂Et SO₂ 4. Cl Cl H H CH₂CO₂H SO₂ 5. CF₃ Cl H H CH₂CO₂Et SO₂ 6. CF₃ Cl H H CH₂CO₂H SO₂ 7. OCH₃ Cl H H CH₂CO₂Et SO₂ 8. OCH₃ Cl H H CH₂CO₂H SO₂ 9. N(CH₃)₂ Cl H H CH₂CO₂Et SO₂ 10. N(CH₃)₂ Cl H H CH₂CO₂H SO₂ 11. CH₃ Cl H H CH₂CO₂Et SO₂ 12. CH₃ Cl H H CH₂CO₂H SO₂ 13. H Cl H H CH₂-tetrazole SO₂ 14. Cl Cl H H CH₂-tetrazole SO₂ 15. CF₃ Cl H H CH₂-tetrazole SO₂ 16. OCH₃ Cl H H CH₂-tetrazole SO₂ 17. N(CH₃)₂ Cl H H CH₂-tetrazole SO₂ 18. CH₃ Cl H H CH₂-tetrazole SO₂ 19. H Cl H H CH(CH₃)CO₂Et SO₂ 20. H Cl H H CH(CH₃)CO₂H SO₂ 21. Cl Cl H H CH(CH₃)CO₂Et SO₂ 22. Cl Cl H H CH(CH₃)CO₂H SO₂ 23. CF₃ Cl H H CH(CH₃)CO₂Et SO₂ 24. CF₃ Cl H H CH(CH₃)CO₂H SO₂ 25. OCH₃ Cl H H CH(CH₃)CO₂Et SO₂ 26. OCH₃ Cl H H CH(CH₃)CO₂H SO₂ 27. N(CH₃)₂ Cl H H CH(CH₃)CO₂Et SO₂ 28. N(CH₃)₂ Cl H H CH(CH₃)CO₂H SO₂ 29. CH₃ Cl H H CH(CH₃)CO₂Et SO₂ 30. CH₃ Cl H H CH(CH₃)CO₂H SO₂ 31. H H Cl H CH₂CO₂Et SO₂ 32. H H Cl H CH₂CO₂H SO₂ 33. Cl H Cl H CH₂CO₂Et SO₂ 34. Cl H Cl H CH₂CO₂H SO₂ 35. CF₃ H Cl H CH₂CO₂Et SO₂ 36. CF₃ H Cl H CH₂CO₂H SO₂ 37. OCH₃ H Cl H CH₂CO₂Et SO₂ 38. OCH₃ H Cl H CH₂CO₂H SO₂ 39. N(CH₃)₂ H Cl H CH₂CO₂Et SO₂ 40. N(CH₃)₂ H Cl H CH₂CO₂H SO₂ 41. CH₃ H Cl H CH₂CO₂Et SO₂ 42. CH₃ H Cl H CH₂CO₂H SO₂ 43. H H Cl H CH₂-tetrazole SO₂ 44. Cl H Cl H CH₂-tetrazole SO₂ 45. CF₃ H Cl H CH₂-tetrazole SO₂ 46. OCH₃ H Cl H CH₂-tetrazole SO₂ 47. N(CH₃)₂ H Cl H CH₂-tetrazole SO₂ 48. CH₃ H Cl H CH₂-tetrazole SO₂ 49. H H Cl H CH(CH₃)CO₂Et SO₂ 50. H H Cl H CH(CH₃)CO₂H SO₂ 51. Cl H Cl H CH(CH₃)CO₂Et SO₂ 52. Cl H Cl H CH(CH₃)CO₂H SO₂ 53. CF₃ H Cl H CH(CH₃)CO₂Et SO₂ 54. CF₃ H Cl H CH(CH₃)CO₂H SO₂ 55. OCH₃ H Cl H CH(CH₃)CO₂Et SO₂ 56. OCH₃ H Cl H CH(CH₃)CO₂H SO₂ 57. N(CH₃)₂ H Cl H CH(CH₃)CO₂Et SO₂ 58. N(CH₃)₂ H Cl H CH(CH₃)CO₂H SO₂ 59. CH₃ H Cl H CH(CH₃)CO₂Et SO₂ 60. CH₃ H Cl H CH(CH₃)CO₂H SO₂ 61. H H Cl H CH₂CONH₂ SO₂ 62. Cl H Cl H CH₂CONH₂ SO₂ 63. CF₃ H Cl H CH₂CONH₂ SO₂ 64. OCH₃ H Cl H CH₂CONH₂ SO₂ 65. N(CH₃)₂ H Cl H CH₂CONH₂ SO₂ 66. CH₃ H Cl H CH₂CONH₂ SO₂ 67. H Cl H OH CH₂CO₂Et SO₂ 68. H Cl H OH CH₂CO₂H SO₂ 69. Cl Cl H OH CH₂CO₂Et SO₂ 70. Cl Cl H OH CH₂CO₂H SO₂ 71. CF₃ Cl H OH CH₂CO₂Et SO₂ 72. CF₃ Cl H OH CH₂CO₂H SO₂ 73. OCH₃ Cl H OH CH₂CO₂Et SO₂ 74. OCH₃ Cl H OH CH₂CO₂H SO₂ 75. N(CH₃)₂ Cl H OH CH₂CO₂Et SO₂ 76. N(CH₃)₂ Cl H OH CH₂CO₂H SO₂ 77. CH₃ Cl H OH CH₂CO₂Et SO₂ 78. CH₃ Cl H OH CH₂CO₂H SO₂ 79. H Cl H OH CH₂-tetrazole SO₂ 80. Cl Cl H OH CH₂-tetrazole SO₂ 81. CF₃ Cl H OH CH₂-tetrazole SO₂ 82. OCH₃ Cl H OH CH₂-tetrazole SO₂ 83. N(CH₃)₂ Cl H OH CH₂-tetrazole SO₂ 84. CH₃ Cl H OH CH₂-tetrazole SO₂ 85. H Cl H OH CH(CH₃)CO₂Et SO₂ 86. H Cl H OH CH(CH₃)CO₂H SO₂ 87. Cl Cl H OH CH(CH₃)CO₂Et SO₂ 88. Cl Cl H OH CH(CH₃)CO₂H SO₂ 89. CF₃ Cl H OH CH(CH₃)CO₂Et SO₂ 90. CF₃ Cl H OH CH(CH₃)CO₂H SO₂ 91. OCH₃ Cl H OH CH(CH₃)CO₂Et SO₂ 92. OCH₃ Cl H OH CH(CH₃)CO₂H SO₂ 93. N(CH₃)₂ Cl H OH CH(CH₃)CO₂Et SO₂ 94. N(CH₃)₂ Cl H OH CH(CH₃)CO₂H SO₂ 95. CH₃ Cl H OH CH(CH₃)CO₂Et SO₂ 96. CH₃ Cl H OH CH(CH₃)CO₂H SO₂ 97. H Cl H OH CH(CH₂OH)CO₂Et SO₂ 98. H Cl H OH CH(CH₂OH)CO₂H SO₂ 99. Cl Cl H OH CH(CH₂OH)CO₂Et SO₂ 100. Cl Cl H OH CH(CH₂OH)CO₂H SO₂ 101. CF₃ Cl H OH CH(CH₂OH)CO₂Et SO₂ 102. CF₃ Cl H OH CH(CH₂OH)CO₂H SO₂ 103. OCH₃ Cl H OH CH(CH₂OH)CO₂Et SO₂ 104. OCH₃ Cl H OH CH(CH₂OH)CO₂H SO₂ 105. N(CH₃)₂ Cl H OH CH(CH₂OH)CO₂Et SO₂ 106. N(CH₃)₂ Cl H OH CH(CH₂OH)CO₂H SO₂ 107. CH₃ Cl H OH CH(CH₂OH)CO₂Et SO₂ 108. CH₃ Cl H OH CH(CH₂OH)CO₂H SO₂ 109. H Cl H OH CH(CH₂OH)CONH₂ SO₂ 110. Cl Cl H OH CH(CH₂OH)CONH₂ SO₂ 111. CF₃ Cl H OH CH(CH₂OH)CONH₂ SO₂ 112. OCH₃ Cl H OH CH(CH₂OH)CONH₂ SO₂ 113. N(CH₃)₂ Cl H OH CH(CH₂OH)CONH₂ SO₂ 114. CH₃ Cl H OH CH(CH₃OH)CONH₂ SO₂ 115. H H Cl OH CH₂CO₂Et SO₂ 116. H H Cl OH CH₂CO₂H SO₂ 117. Cl H Cl OH CH₂CO₂Et SO₂ 118. Cl H Cl OH CH₂CO₂H SO₂ 119. CF₃ H Cl OH CH₂CO₂Et SO₂ 120. CF₃ H Cl OH CH₂CO₂H SO₂ 121. OCH₃ H Cl OH CH₂CO₂Et SO₂ 122. OCH₃ H Cl OH CH₂CO₂H SO₂ 123. N(CH₃)₂ H Cl OH CH₂CO₂Et SO₂ 124. N(CH₃)₂ H Cl OH CH₂CO₂H SO₂ 125. CH₃ H Cl OH CH₂CO₂Et SO₂ 126. CH₃ H Cl OH CH₂CO₂H SO₂ 127. H H Cl OH CH₂-tetrazole SO₂ 128. Cl H Cl OH CH₂-tetrazole SO₂ 129. CF₃ H Cl OH CH₂-tetrazole SO₂ 130. OCH₃ H Cl OH CH₂-tetrazole SO₂ 131. N(CH₃)₂ H Cl OH CH₂-tetrazole SO₂ 132. CH₃ H Cl OH CH₂-tetrazole SO₂ 133. H H Cl OH CH(CH₃)CO₂Et SO₂ 134. H H Cl OH CH(CH₃)CO₂H SO₂ 135. Cl H Cl OH CH(CH₃)CO₂Et SO₂ 136. Cl H Cl OH CH(CH₃)CO₂H SO₂ 137. CF₃ H Cl OH CH(CH₃)CO₂Et SO₂ 138. CF₃ H Cl OH CH(CH₃)CO₂H SO₂ 139. OCH₃ H Cl OH CH(CH₃)CO₂Et SO₂ 140. OCH₃ H Cl OH CH(CH₃)CO₂H SO₂ 141. N(CH₃)₂ H Cl OH CH(CH₃)CO₂Et SO₂ 142. N(CH₃)₂ H Cl OH CH(CH₃)CO₂H SO₂ 143. CH₃ H Cl OH CH(CH₃)CO₂Et SO₂ 144. CH₃ H Cl OH CH(CH₃)CO₂H SO₂ 145. H H Cl OH CH₂CONH₂ SO₂ 146. Cl H Cl OH CH₂CONH₂ SO₂ 147. CF₃ H Cl OH CH₂CONH₂ SO₂ 148. OCH₃ H Cl OH CH₂CONH₂ SO₂ 149. N(CH₃)₂ H Cl OH CH₂CONH₂ SO₂ 150. CH₃ H Cl OH CH₂CONH₂ SO₂ 151. H H Cl OH CH(CH₂OH)CO₂Et SO₂ 152. H H Cl OH CH(CH₂OH)CO₂H SO₂ 153. Cl H Cl OH CH(CH₂OH)CO₂Et SO₂ 154. Cl H Cl OH CH(CH₂OH)CO₂H SO₂ 155. CF₃ H Cl OH CH(CH₂OH)CO₂Et SO₂ 156. CF₃ H Cl OH CH(CH₂OH)CO₂H SO₂ 157. OCH₃ H Cl OH CH(CH₂OH)CO₂Et SO₂ 158. OCH₃ H Cl OH CH(CH₂OH)CO₂H SO₂ 159. N(CH₃)₂ H Cl OH CH(CH₂OH)CO₂Et SO₂ 160. N(CH₃)₂ H Cl OH CH(CH₂OH)CO₂H SO₂ 161. CH₃ H Cl OH CH(CH₂OH)CO₂Et SO₂ 162. CH₃ H Cl OH CH(CH₂OH)CO₂H SO₂ 163. H H Cl OH CH(CH₂OH)CONH₂ SO₂ 164. Cl H Cl OH CH(CH₂OH)CONH₂ SO₂ 165. CF₃ H Cl OH CH(CH₂OH)CONH₂ SO₂ 166. OCH₃ H Cl OH CH(CH₂OH)CONH₂ SO₂ 167. N(CH₃)₂ H Cl OH CH(CH₂OH)CONH₂ SO₂ 168. CH₃ H Cl OH CH(CH₂OH)CONH₂ SO₂ 169. H Cl H H CH₂CO₂Et CO 170. H Cl H H CH₂CO₂H CO 171. Cl Cl H H CH₂CO₂Et CO 172. Cl Cl H H CH₂CO₂H CO 173. CF₃ Cl H H CH₂CO₂Et CO 174. CF₃ Cl H H CH₂CO₂H CO 175. OCH₃ Cl H H CH₂CO₂Et CO 176. OCH₃ Cl H H CH₂CO₂H CO 177. N(CH₃)₂ Cl H H CH₂CO₂Et CO 178. N(CH₃)₂ Cl H H CH₂CO₂H CO 179. CH₃ Cl H H CH₂CO₂Et CO 180. CH₃ Cl H H CH₂CO₂H CO 181. H Cl H H CH₂-tetrazole CO 182. Cl Cl H H CH₂-tetrazole CO 183. CF₃ Cl H H CH₂-tetrazole CO 184. OCH₃ Cl H H CH₂-tetrazole CO 185. N(CH₃)₂ Cl H H CH₂-tetrazole CO 186. CH₃ Cl H H CH₂-tetrazole CO 187. H Cl H H CH(CH₃)CO₂Et CO 188. H Cl H H CH(CH₃)CO₂H CO 189. Cl Cl H H CH(CH₃)CO₂Et CO 190. Cl Cl H H CH(CH₃)CO₂H CO 191. CF₃ Cl H H CH(CH₃)CO₂Et CO 192. CF₃ Cl H H CH(CH₃)CO₂H CO 193. OCH₃ Cl H H CH(CH₃)CO₂Et CO 194. OCH₃ Cl H H CH(CH₃)CO₂H CO 195. N(CH₃)₂ Cl H H CH(CH₃)CO₂Et CO 196. N(CH₃)₂ Cl H H CH(CH₃)CO₂H CO 197. CH₃ Cl H H CH(CH₃)CO₂Et CO 198. CH₃ Cl H H CH(CH₃)CO₂H CO 199. H H Cl H CH₂CO₂Et CO 200. H H Cl H CH₂CO₂H CO 201. Cl H Cl H CH₂CO₂Et CO 202. Cl H Cl H CH₂CO₂H CO 203. CF₃ H Cl H CH₂CO₂Et CO 204. CF₃ H Cl H CH₂CO₂H CO 205. OCH₃ H Cl H CH₂CO₂Et CO 206. OCH₃ H Cl H CH₂CO₂H CO 207. N(CH₃)₂ H Cl H CH₂CO₂Et CO 208. N(CH₃)₂ H Cl H CH₂CO₂H CO 209. CH₃ H Cl H CH₂CO₂Et CO 210. CH₃ H Cl H CH₂CO₂H CO 211. H H Cl H CH₂-tetrazole CO 212. Cl H Cl H CH₂-tetrazole CO 213. CF₃ H Cl H CH₂-tetrazole CO 214. OCH₃ H Cl H CH₂-tetrazole CO 215. N(CH₃)₂ H Cl H CH₂-tetrazole CO 216. CH₃ H Cl H CH₂-tetrazole CO 217. H H Cl H CH(CH₃)CO₂Et CO 218. H H Cl H CH(CH₃)CO₂H CO 219. Cl H Cl H CH(CH₃)CO₂Et CO 220. Cl H Cl H CH(CH₃)CO₂H CO 221. CF₃ H Cl H CH(CH₃)CO₂Et CO 222. CF₃ H Cl H CH(CH₃)CO₂H CO 223. OCH₃ H Cl H CH(CH₃)CO₂Et CO 224. OCH₃ H Cl H CH(CH₃)CO₂H CO 225. N(CH₃)₂ H Cl H CH(CH₃)CO₂Et CO 226. N(CH₃)₂ H Cl H CH(CH₃)CO₂H CO 227. CH₃ H Cl H CH(CH₃)CO₂Et CO 228. CH₃ H Cl H CH(CH₃)CO₂H CO 229. H H Cl H CH₂CONH₂ CO 230. Cl H Cl H CH₂CONH₂ CO 231. CF₃ H Cl H CH₂CONH₂ CO 232. OCH₃ H Cl H CH₂CONH₂ CO 233. N(CH₃)₂ H Cl H CH₂CONH₂ CO 234. CH₃ H Cl H CH₂CONH₂ CO 235. H Cl H OH CH₂CO₂Et CO 236. H Cl H OH CH₂CO₂H CO 237. Cl Cl H OH CH₂CO₂Et CO 238. Cl Cl H OH CH₂CO₂H CO 239. CF₃ Cl H OH CH₂CO₂Et CO 240. CF₃ Cl H OH CH₂CO₂H CO 241. OCH₃ Cl H OH CH₂CO₂Et CO 242. OCH₃ Cl H OH CH₂CO₂H CO 243. N(CH₃)₂ Cl H OH CH₂CO₂Et CO 244. N(CH₃)₂ Cl H OH CH₂CO₂H CO 245. CH₃ Cl H OH CH₂CO₂Et CO 246. CH₃ Cl H OH CH₂CO₂H CO 247. H Cl H OH CH₂-tetrazole CO 248. Cl Cl H OH CH₂-tetrazole CO 249. CF₃ Cl H OH CH₂-tetrazole CO 250. OCH₃ Cl H OH CH₂-tetrazole CO 251. N(CH₃)₂ Cl H OH CH₂-tetrazole CO 252. CH₃ Cl H OH CH₂-tetrazole CO 253. H Cl H OH CH(CH₃)CO₂Et CO 254. H Cl H OH CH(CH₃)CO₂H CO 255. Cl Cl H OH CH(CH₃)CO₂Et CO 256. Cl Cl H OH CH(CH₃)CO₂H CO 257. CF₃ Cl H OH CH(CH₃)CO₂Et CO 258. CF₃ Cl H OH CH(CH₃)CO₂H CO 259. OCH₃ Cl H OH CH(CH₃)CO₂Et CO 260. OCH₃ Cl H OH CH(CH₃)CO₂H CO 261. N(CH₃)₂ Cl H OH CH(CH₃)CO₂Et CO 262. N(CH₃)₂ Cl H OH CH(CH₃)CO₂H CO 263. CH₃ Cl H OH CH(CH₃)CO₂Et CO 264. CH₃ Cl H OH CH(CH₃)CO₂H CO 265. H Cl H OH CH(CH₂OH)CO₂Et CO 266. H Cl H OH CH(CH₂OH)CO₂H CO 267. Cl Cl H OH CH(CH₂OH)CO₂Et CO 268. Cl Cl H OH CH(CH₂OH)CO₂H CO 269. CF₃ Cl H OH CH(CH₂OH)CO₂Et CO 270. CF₃ Cl H OH CH(CH₂OH)CO₂H CO 271. OCH₃ Cl H OH CH(CH₂OH)CO₂Et CO 272. OCH₃ Cl H OH CH(CH₂OH)CO₂H CO 273. N(CH₃)₂ Cl H OH CH(CH₂OH)CO₂Et CO 274. N(CH₃)₂ Cl H OH CH(CH₂OH)CO₂H CO 275. CH₃ Cl H OH CH(CH₂OH)CO₂Et CO 276. CH₃ Cl H OH CH(CH₂OH)CO₂H CO 277. H Cl H OH CH(CH₂OH)CONH₂ CO 278. Cl Cl H OH CH(CH₂OH)CONH₂ CO 279. CF₃ Cl H OH CH(CH₂OH)CONH₂ CO 280. OCH₃ Cl H OH CH(CH₂OH)CONH₂ CO 281. N(CH₃)₂ Cl H OH CH(CH₂OH)CONH₂ CO 282. CH₃ Cl H OH CH(CH₂OH)CONH₂ CO 283. H H Cl OH CH₂CO₂Et CO 284. H H Cl OH CH₂CO₂H CO 285. Cl H Cl OH CH₂CO₂Et CO 286. Cl H Cl OH CH₂CO₂H CO 287. CF₃ H Cl OH CH₂CO₂Et CO 288. CF₃ H Cl OH CH₂CO₂H CO 289. OCH₃ H Cl OH CH₂CO₂Et CO 290. OCH₃ H Cl OH CH₂CO₂H CO 291. N(CH₃)₂ H Cl OH CH₂CO₂Et CO 292. N(CH₃)₂ H Cl OH CH₂CO₂H CO 293. CH₃ H Cl OH CH₂CO₂Et CO 294. CH₃ H Cl OH CH₂CO₂H CO 295. H H Cl OH CH₂-tetrazole CO 296. Cl H Cl OH CH₂-tetrazole CO 297. CF₃ H Cl OH CH₂-tetrazole CO 298. OCH₃ H Cl OH CH₂-tetrazole CO 299. N(CH₃)₂ H Cl OH CH₂-tetrazole CO 300. CH₃ H Cl OH CH₂-tetrazole CO 301. H H Cl OH CH(CH₃)CO₂Et CO 302. H H Cl OH CH(CH₃)CO₂H CO 303. Cl H Cl OH CH(CH₃)CO₂Et CO 304. Cl H Cl OH CH(CH₃)CO₂H CO 305. CF₃ H Cl OH CH(CH₃)CO₂Et CO 306. CF₃ H Cl OH CH(CH₃)CO₂H CO 307. OCH₃ H Cl OH CH(CH₃)CO₂Et CO 308. OCH₃ H Cl OH CH(CH₃)CO₂H CO 309. N(CH₃)₂ H Cl OH CH(CH₃)CO₂Et CO 310. N(CH₃)₂ H Cl OH CH(CH₃)CO₂H CO 311. CH₃ H Cl OH CH(CH₃)CO₂Et CO 312. CH₃ H Cl OH CH(CH₃)CO₂H CO 313. H H Cl OH CH₂CONH₂ CO 314. Cl H Cl OH CH₂CONH₂ CO 315. CF₃ H Cl OH CH₂CONH₂ CO 316. OCH₃ H Cl OH CH₂CONH₂ CO 317. N(CH₃)₂ H Cl OH CH₂CONH₂ CO 318. CH₃ H Cl OH CH₂CONH₂ CO 319. H H Cl OH CH(CH₂OH)CO₂Et CO 320. H H Cl OH CH(CH₂OH)CO₂H CO 321. Cl H Cl OH CH(CH₂OH)CO₂Et CO 322. Cl H Cl OH CH(CH₂OH)CO₂H CO 323. CF₃ H Cl OH CH(CH₂OH)CO₂Et CO 324. CF₃ H Cl OH CH(CH₂OH)CO₂H CO 325. OCH₃ H Cl OH CH(CH₂OH)CO₂Et CO 326. OCH₃ H Cl OH CH(CH₂OH)CO₂H CO 327. N(CH₃)₂ H Cl OH CH(CH₂OH)CO₂Et CO 328. N(CH₃)₂ H Cl OH CH(CH₂OH)CO₂H CO 329. CH₃ H Cl OH CH(CH₂OH)CO₂Et CO 330. CH₃ H Cl OH CH(CH₂OH)CO₂H CO 331. H H Cl OH CH(CH₂OH)CONH₂ CO 332. Cl H Cl OH CH(CH₂OH)CONH₂ CO 333. CF₃ H Cl OH CH(CH₂OH)CONH₂ CO 334. OCH₃ H Cl OH CH(CH₂OH)CONH₂ CO 335. N(CH₃)₂ H Cl OH CH(CH₂OH)CONH₂ CO 336. CH₃ H Cl OH CH(CH₂OH)CONH₂ CO

TABLE 3

Ex. # X″ Z Q n M 1. Et(OCH₂CH₂)_(n)O H H 2 SO₂ 2. Et(OCH₂CH₂)_(n)O H H 3 SO₂ 3. Et(OCH₂CH₂)_(n)O H H 4 SO₂ 4. Et(OCH₂CH₂)_(n)O H H 5 SO₂ 5. Et(OCH₂CH₂)_(n)O H H 6 SO₂ 6. H(OCH₂CH₂)_(n)O H H 2 SO₂ 7. H(OCH₂CH₂)_(n)O H H 3 SO₂ 8. H(OCH₂CH₂)_(n)O H H 4 SO₂ 9. H(OCH₂CH₂)_(n)O H H 5 SO₂ 10. H(OCH₂CH₂)_(n)O H H 6 SO₂ 11. Et(OCH₂CH₂)_(n)O H H 2 CO 12. Et(OCH₂CH₂)_(n)O H H 3 CO 13. Et(OCH₂CH₂)_(n)O H H 4 CO 14. Et(OCH₂CH₂)_(n)O H H 5 CO 15. Et(OCH₂CH₂)_(n)O H H 6 CO 16. H(OCH₂CH₂)_(n)O H H 2 CO 17. H(OCH₂CH₂)_(n)O H H 3 CO 18. H(OCH₂CH₂)_(n)O H H 4 CO 19. H(OCH₂CH₂)_(n)O H H 5 CO 20. H(OCH₂CH₂)_(n)O H H 6 CO 21. Et(OCH₂CH₂)_(n)O H H 2 SO₂ 22. Et(OCH₂CH₂)_(n)O H H 3 SO₂ 23. Et(OCH₂CH₂)_(n)O H H 4 SO₂ 24. Et(OCH₂CH₂)_(n)O H H 5 SO₂ 25. Et(OCH₂CH₂)_(n)O H H 6 SO₂ 26. H(OCH₂CH₂)_(n)O H H 2 SO₂ 27. H(OCH₂CH₂)_(n)O H H 3 SO₂ 28. H(OCH₂CH₂)_(n)O H H 4 SO₂ 29. H(OCH₂CH₂)_(n)O H H 5 SO₂ 30. H(OCH₂CH₂)_(n)O H H 6 SO₂ 31. Et(OCH₂CH₂)_(n)O H H 2 CO 32. Et(OCH₂CH₂)_(n)O H H 3 CO 33. Et(OCH₂CH₂)_(n)O H H 4 CO 34. Et(OCH₂CH₂)_(n)O H H 5 CO 35. Et(OCH₂CH₂)_(n)O H H 6 CO 36. H(OCH₂CH₂)_(n)O H H 2 CO 37. H(OCH₂CH₂)_(n)O H H 3 CO 38. H(OCH₂CH₂)_(n)O H H 4 CO 39. H(OCH₂CH₂)_(n)O H H 5 CO 40. H(OCH₂CH₂)_(n)O H CH₃ 6 CO 41. Et(OCH₂CH₂)_(n)O H CH₃ 2 SO₂ 42. Et(OCH₂CH₂)_(n)O H CH₃ 3 SO₂ 43. Et(OCH₂CH₂)_(n)O H CH₃ 4 SO₂ 44. Et(OCH₂CH₂)_(n)O H CH₃ 5 SO₂ 45. Et(OCH₂CH₂)_(n)O H CH₃ 6 SO₂ 46. H(OCH₂CH₂)_(n)O H CH₃ 2 SO₂ 47. H(OCH₂CH₂)_(n)O H CH₃ 3 SO₂ 48. H(OCH₂CH₂)_(n)O H CH₃ 4 SO₂ 49. H(OCH₂CH₂)_(n)O H CH₃ 5 SO₂ 50. H(OCH₂CH₂)_(n)O H CH₃ 6 SO₂ 51. Et(OCH₂CH₂)_(n)O H CH₃ 2 CO 52. Et(OCH₂CH₂)_(n)O H CH₃ 3 CO 53. Et(OCH₂CH₂)_(n)O H CH₃ 4 CO 54. Et(OCH₂CH₂)_(n)O H CH₃ 5 CO 55. Et(OCH₂CH₂)_(n)O H CH₃ 6 CO 56. H(OCH₂CH₂)_(n)O H CH₃ 2 CO 57. H(OCH₂CH₂)_(n)O H CH₃ 3 CO 58. H(OCH₂CH₂)_(n)O H CH₃ 4 CO 59. H(OCH₂CH₂)_(n)O H CH₃ 5 CO 60. H(OCH₂CH₂)_(n)O H CH₃ 6 CO 61. Et(OCH₂CH₂)_(n)O H CH₃ 2 SO₂ 62. Et(OCH₂CH₂)_(n)O H CH₃ 3 SO₂ 63. Et(OCH₂CH₂)_(n)O H CH₃ 4 SO₂ 64. Et(OCH₂CH₂)_(n)O H CH₃ 5 SO₂ 65. Et(OCH₂CH₂)_(n)O H CH₃ 6 SO₂ 66. H(OCH₂CH₂)_(n)O H CH₃ 2 SO₂ 67. H(OCH₂CH₂)_(n)O H CH₃ 3 SO₂ 68. H(OCH₂CH₂)_(n)O H CH₃ 4 SO₂ 69. H(OCH₂CH₂)_(n)O H CH₃ 5 SO₂ 70. H(OCH₂CH₂)_(n)O H CH₃ 6 SO₂ 71. Et(OCH₂CH₂)_(n)O H CH₃ 2 CO 72. Et(OCH₂CH₂)_(n)O H CH₃ 3 CO 73. Et(OCH₂CH₂)_(n)O H CH₃ 4 CO 74. Et(OCH₂CH₂)_(n)O H CH₃ 5 CO 75. Et(OCH₂CH₂)_(n)O H CH₃ 6 CO 76. H(OCH₂CH₂)_(n)O H CH₃ 2 CO 77. H(OCH₂CH₂)_(n)O H CH₃ 3 CO 78. H(OCH₂CH₂)_(n)O H CH₃ 4 CO 79. H(OCH₂CH₂)_(n)O H CH₃ 5 CO 80. H(OCH₂CH₂)_(n)O H CH₃ 6 CO 81. Et(OCH₂CH₂)_(n)O OH H 2 SO₂ 82. Et(OCH₂CH₂)_(n)O OH H 3 SO₂ 83. Et(OCH₂CH₂)_(n)O OH H 4 SO₂ 84. Et(OCH₂CH₂)_(n)O OH H 5 SO₂ 85. Et(OCH₂CH₂)_(n)O OH H 6 SO₂ 86. H(OCH₂CH₂)_(n)O OH H 2 SO₂ 87. H(OCH₂CH₂)_(n)O OH H 3 SO₂ 88. H(OCH₂CH₂)_(n)O OH H 4 SO₂ 89. H(OCH₂CH₂)_(n)O OH H 5 SO₂ 90. H(OCH₂CH₂)_(n)O OH H 6 SO₂ 91. Et(OCH₂CH₂)_(n)O OH H 2 CO 92. Et(OCH₂CH₂)_(n)O OH H 3 CO 93. Et(OCH₂CH₂)_(n)O OH H 4 CO 94. Et(OCH₂CH₂)_(n)O OH H 5 CO 95. Et(OCH₂CH₂)_(n)O OH H 6 CO 96. H(OCH₂CH₂)_(n)O OH H 2 CO 97. H(OCH₂CH₂)_(n)O OH H 3 CO 98. H(OCH₂CH₂)_(n)O OH H 4 CO 99. H(OCH₂CH₂)_(n)O OH H 5 CO 100. H(OCH₂CH₂)_(n)O OH H 6 CO 101. Et(OCH₂CH₂)_(n)O OH H 2 SO₂ 102. Et(OCH₂CH₂)_(n)O OH H 3 SO₂ 103. Et(OCH₂CH₂)_(n)O OH H 4 SO₂ 104. Et(OCH₂CH₂)_(n)O OH H 5 SO₂ 105. Et(OCH₂CH₂)_(n)O OH H 6 SO₂ 106. H(OCH₂CH₂)_(n)O OH H 2 SO₂ 107. H(OCH₂CH₂)_(n)O OH H 3 SO₂ 108. H(OCH₂CH₂)_(n)O OH H 4 SO₂ 109. H(OCH₂CH₂)_(n)O OH H 5 SO₂ 110. H(OCH₂CH₂)_(n)O OH H 6 SO₂ 111. Et(OCH₂CH₂)_(n)O OH H 2 CO 112. Et(OCH₂CH₂)_(n)O OH H 3 CO 113. Et(OCH₂CH₂)_(n)O OH H 4 CO 114. Et(OCH₂CH₂)_(n)O OH H 5 CO 115. Et(OCH₂CH₂)_(n)O OH H 6 CO 116. H(OCH₂CH₂)_(n)O OH H 2 CO 117. H(OCH₂CH₂)_(n)O OH H 3 CO 118. H(OCH₂CH₂)_(n)O OH H 4 CO 119. H(OCH₂CH₂)_(n)O OH H 5 CO 120. H(OCH₂CH₂)_(n)O OH CH₃ 6 CO 121. Et(OCH₂CH₂)_(n)O OH CH₃ 2 SO₂ 122. Et(OCH₂CH₂)_(n)O OH CH₃ 3 SO₂ 123. Et(OCH₂CH₂)_(n)O OH CH₃ 4 SO₂ 124. Et(OCH₂CH₂)_(n)O OH CH₃ 5 SO₂ 125. Et(OCH₂CH₂)_(n)O OH CH₃ 6 SO₂ 126. H(OCH₂CH₂)_(n)O OH CH₃ 2 SO₂ 127. H(OCH₂CH₂)_(n)O OH CH₃ 3 SO₂ 128. H(OCH₂CH₂)_(n)O OH CH₃ 4 SO₂ 129. H(OCH₂CH₂)_(n)O OH CH₃ 5 SO₂ 130. H(OCH₂CH₂)_(n)O OH CH₃ 6 SO₂ 131. Et(OCH₂CH₂)_(n)O OH CH₃ 2 CO 132. Et(OCH₂CH₂)_(n)O OH CH₃ 3 CO 133. Et(OCH₂CH₂)_(n)O OH CH₃ 4 CO 134. Et(OCH₂CH₂)_(n)O OH CH₃ 5 CO 135. Et(OCH₂CH₂)_(n)O OH CH₃ 6 CO 136. H(OCH₂CH₂)_(n)O OH CH₃ 2 CO 137. H(OCH₂CH₂)_(n)O OH CH₃ 3 CO 138. H(OCH₂CH₂)_(n)O OH CH₃ 4 CO 139. H(OCH₂CH₂)_(n)O OH CH₃ 5 CO 140. H(OCH₂CH₂)_(n)O OH CH₃ 6 CO 141. Et(OCH₂CH₂)_(n)O OH CH₃ 2 SO₂ 142. Et(OCH₂CH₂)_(n)O OH CH₃ 3 SO₂ 143. Et(OCH₂CH₂)_(n)O OH CH₃ 4 SO₂ 144. Et(OCH₂CH₂)_(n)O OH CH₃ 5 SO₂ 145. Et(OCH₂CH₂)_(n)O OH CH₃ 6 SO₂ 146. H(OCH₂CH₂)_(n)O OH CH₃ 2 SO₂ 147. H(OCH₂CH₂)_(n)O OH CH₃ 3 SO₂ 148. H(OCH₂CH₂)_(n)O OH CH₃ 4 SO₂ 149. H(OCH₂CH₂)_(n)O OH CH₃ 5 SO₂ 150. H(OCH₂CH₂)_(n)O OH CH₃ 6 SO₂ 151. Et(OCH₂CH₂)_(n)O OH CH₃ 2 CO 152. Et(OCH₂CH₂)_(n)O OH CH₃ 3 CO 153. Et(OCH₂CH₂)_(n)O OH CH₃ 4 CO 154. Et(OCH₂CH₂)_(n)O OH CH₃ 5 CO 155. Et(OCH₂CH₂)_(n)O OH CH₃ 6 CO 156. H(OCH₂CH₂)_(n)O OH CH₃ 2 CO 157. H(OCH₂CH₂)_(n)O OH CH₃ 3 CO 158. H(OCH₂CH₂)_(n)O OH CH₃ 4 CO 159. H(OCH₂CH₂)_(n)O OH CH₃ 5 CO 160. H(OCH₂CH₂)_(n)O OH CH₃ 6 CO

Numerous modifications and variations of the present invention are possible in light of the above teachings. It is therefore to be understood that within the scope of the appended claims, the invention may be practiced otherwise that as specifically described herein. 

1. A compound of of Formula I or a stereoisomer or pharmaceutically acceptable salt thereof:

wherein: X, Y, X′, Y′, X″, and Y″ are independently selected from: H, C₁₋₆ alkyl, halogen, CF₃, O—C₁₋₆ alkyl, NO₂, NR₂, O(CH₂)_(n)CO₂R, OCH₂CH═CHCO₂R, CH₂O(CH₂),CO₂R, CH₂OCH₂CH═CHCO₂R, O(CH₂)_(n)PO(OR)₂, CH₂O(CH₂)_(n)PO(OR)₂, NR^(a)(CH₂)_(n)CO₂R, NR^(a)(CH₂)_(n)PO(OR)₂, NR^(a)CH₂CH═CHCO₂R, NR^(a)SO₂R, NR^(a)CO(CH₂)_(n)CO₂R, NR^(a)CO(CH₂)_(n)CONR^(a) ₂, O(CH₂)_(n)C₆H₄CO₂R, O(CH₂)_(n)C₆H₄(CH₂)_(n)CO₂R, CH₂O(CH₂)_(n)C₆H₄CO₂R, O(CH₂)_(n)C₆H₄CONR^(a) ₂, O(CH₂)_(n)C₆H₄(CH₂)_(n)CONR^(a) ₂, O(CH₂)_(n)C₆H₄-tetrazole, CH₂O(CH₂)_(n)C₆H₄CONR^(a) ₂, CH₂O(CH₂)_(n)C₆H₄-tetrazole, O(CH₂)_(n)C₆H₄(CH₂)_(n)-tetrazole, NR^(a)(CH₂)_(n)C₆H₄CO₂R, CH₂NR^(a)(CH₂)_(n)C₆H₄CO₂R, NR^(a)(CH₂)_(n)C₆H₄(CH₂)_(n)CO₂R, NR^(a)(CH₂)_(n)C₆H₄CONR^(a) ₂, CH₂NR^(a)(CH₂)_(n)C₆H₄CONR^(a) ₂, NR^(a)(CH₂)_(n)C₆H₄(CH₂)_(n)CONR^(a) ₂, NR^(a)(CH₂)_(n)C₆H₄-tetrazole, CH₂NR^(a)(CH₂)_(n)C₆H₄-tetrazole, NR^(a)(CH₂)_(n) C₆H₄(CH₂)_(n)-tetrazole, C(NH)NR₂, (CH₂)_(n)C(NH)NR₂, O(CH₂)_(n)CONR₂, O(CH₂)_(n)C(NH)NR₂, CH₂O(CH₂)_(n)CONR^(a) ₂, NR^(a)(CH₂)_(n)CONR^(a) ₂, OCH₂CH═CHCONR^(a) ₂, CH₂OCH₂CH═CHCONR^(a) ₂, NR^(a)CH₂CH═CHCONR₂, (CH₂)_(m)-tetrazole, O(CH₂)_(n)-tetrazole, O(CH₂CH₂O)_(p)R, NR^(a)(CH₂CH₂O)_(p)R, and SO₂NHCH₃; Z is selected from: H, C₁₋₆ alkyl, OH, O—C₁₋₆ alkyl, O(CH₂CH₂O)_(p)R, OC(O)—C₁₋₆ alkyl, O(CH₂)_(n)CO₂R, OCH₂CH═CHCO₂R, O(CH₂)_(n)PO(OR)₂, O(CH₂)_(n)CONH₂, O(CH₂)_(n)C(NH)NH₂, OCH₂CH═CHCONH₂, O(CH₂)_(n)-phenyl-(CH₂)_(m)CO₂R, and O(CH₂)_(n)-phenyl-(CH₂)_(m)-tetrazole; Q is selected from: H, C₁₋₆ alkyl, (CH₂)_(n)-aryl, (CH₂CH₂O)_(p)R, (CH₂)_(n)-heteroaryl, (CH₂)_(n)-tetrazole, —CHA(CH₂)_(m)C(O)NR₂, CHA(CH₂)_(m)CO₂R, (CH₂)_(n)-phenyl-(CH₂)_(m)CO₂R, (CH₂)_(n)-phenyl-(CH₂)_(m)CONH₂, and (CH₂)_(m)-phenyl-(CH₂)_(m)-tetrazole, wherein the heteroaryl, phenyl, and aryl are substituted with 0-3 groups selected from H, C₁₋₄ alkyl, halogen, CF₃, O—C₁₋₄ alkyl, and NO₂; M is C═O or SO₂; R is independently selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl; R^(a) is independently selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl; A is selected from H, C₁₋₆ alkyl, (CH₂)_(m)C₃₋₆-cycloalkyl, CH₂OH, CH(CH₃)OH, and (CH₂)_(m)-phenyl, wherein the phenyl is substituted with 0-3 groups selected from H, C₁₋₄ alkyl, halogen, CF₃, O—C₁₋₄ alkyl, and NO₂; p is selected from 2-12; m is selected from 0, 1, 2, and 3; and, n is selected from 1, 2, and 3; provided that at least one of the following is satisfied: (a) at least one of X, Y, X′, Y′, X″, and Y″ is other than H, C₁₋₆ alkyl, halogen, CF₃, O—C₁₋₆ alkyl, NO₂, and NR₂; (b) Z is other than H, C₁₋₆ alkyl, OH, O—C₁₋₆ alkyl, acetyloxy, and propionyloxy; or, (c) Q is other than H, C₁₋₆ alkyl, (CH₂)_(n)-heteroaryl, and (CH₂)_(n)-aryl.
 2. A compound of claim 1, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein: at least one of X, Y, X′, Y′, X″, and Y″ is independently selected from: O(CH₂)_(n)CO₂R, OCH₂CH═CHCO₂R, CH₂O(CH₂)_(n)CO₂R, CH₂OCH₂CH═CHCO₂R, O(CH₂)_(n)PO(OR)₂, CH₂O(CH₂)_(n)PO(OR)₂, NR^(a)(CH₂)_(n)CO₂R, NR^(a)(CH₂)_(n)PO(OR)₂, NR^(a)CH₂CH═CHCO₂R, NR^(a)CO(CH₂)_(n)CONR^(a) ₂, NR^(a)SO₂CH₃, NR^(a)CO(CH₂)_(n)CO₂R, O(CH₂)_(n)C₆H₄CO₂R, O(CH₂)_(n)C₆H₄(CH₂)_(n)CO₂R, CH₂O(CH₂)_(n)C₆H₄CO₂R, O(CH₂)_(n)C₆H₄CONH₂, O(CH₂)_(n)C₆H₄(CH₂)_(n)CONR^(a) ₂, O(CH₂)_(n)C₆H₄-tetrazole, CH₂O(CH₂)_(n)C₆H₄CONH₂, CH₂O(CH₂)_(n)C₆H₄-tetrazole, O(CH₂)_(n)C₆H₄(CH₂)_(n)-tetrazole, NR^(a)(CH₂)_(n)C₆H₄CO₂R, CH₂NR^(a)(CH₂)_(n)C₆H₄CO₂R, NR^(a)(CH₂)_(n)C₆H₄(CH₂)_(n)CO₂R, NR^(a)(CH₂)_(n)C₆l H₄CONR^(a) ₂, CH₂NR^(a)(CH₂)_(n)C₆H₄CONR^(a) ₂, NR^(a)(CH₂)_(n)C₆H₄(CH₂)_(n)CONR^(a) ₂, NR^(a)(CH₂)_(n)C₆H₄-tetrazole, CH₂NR^(a)(CH₂)_(n)C₆H₄-tetrazole, NR^(a)(CH₂)_(n)C₆H₄(CH₂ _() n)-tetrazole, C(NH)NR₂, (CH₂)_(n)C(NH)NR₂, O(CH₂)_(n)CONR^(a) ₂, O(CH₂)_(n)C(NH)NH₂, CH₂O(CH₂)_(n)CONR^(a) ₂, NR^(a)(CH₂)_(n)CONH₂, OCH₂CH═CHCONR^(a) ₂, CH₂OCH₂CH═CHCONR^(a) ₂, NR^(a)CH₂CH═CHCONR^(a) ₂, (CH₂)_(m)-tetrazole, O(CH₂)_(n)-tetrazole, O(CH₂CH₂O)_(p)R, NR^(a)(CH₂CH₂O)_(p)R, and SO₂NHCH₃; the other of X, Y, X′, Y′, X″, and Y″ are independently selected from: H, C₁₋₄ alkyl, halogen, CF₃, O—C₁₋₄ alkyl, NO₂, and NR₂; R is independently selected from H, C₁₋₄ alkyl, C₂₋₄ alkenyl, and C₂₋₄ alkynyl; R^(a) is independently selected from H, C₁₋₄ alkyl, C₂₋₄ alkenyl, and C₂₋₄ alkynyl; Z is selected from: H, C₁₋₄ alkyl, OH, O—C₁₋₄ alkyl, acetyloxy, and propionyloxy; Q is selected from: is selected from H, C₁₋₄ alkyl, (CH₂CH₂O)_(p)R, (CH₂)_(n)-heteroaryl, and (CH₂)_(m)-aryl, wherein the heteroaryl and aryl are substituted with 0-3 groups selected from H, C₁₋₄ alkyl, halogen, CF₃, O—C₁₋₄ alkyl, and NO₂; M is C═O or SO₂; p is selected from 2-12; m is independently selected from 0, 1, 2, and 3; and, n is independently selected from 1, 2, and
 3. 3. A compound of claim 2, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein: X, Y, X′, Y′, X″, and Y″ are independently selected from: H, C₁₋₄ alkyl, halogen, CF₃, O—C₁₋₄ alkyl, NO₂, O(CH₂CH₂O)_(p)R, NR^(a)(CH₂CH₂O)_(p)R, and NR₂; Z is selected from: O(CH₂CH₂O)_(p)R, O(CH₂)_(n)CO₂R, OCH₂CH═CHCO₂R, O(CH₂)_(n)PO(OR)₂, O(CH₂)_(n)CONH₂, O(CH₂)_(n)C(NH)NH₂, OCH₂CH═CHCONH₂, O(CH₂)_(n)-phenyl-(CH₂)_(m)CO₂R, and O(CH₂)_(n)-phenyl-(CH₂)_(m)-tetrazole; Q is selected from: H, C₁₋₄ alkyl, (CH₂CH₂O)_(p)R, (CH₂)_(n)-heteroaryl, and (CH₂)_(n)-aryl , wherein the heteroaryl and aryl are substituted with 0-3 groups selected from H, C₁₋₄ alkyl, halogen, CF₃, O—C₁₋₄ alkyl, and NO₂; M is C═O or SO₂; R is independently selected from H, C₁₋₄ alkyl, C₂₋₄ alkenyl, and C₂₋₄ alkynyl; p is selected from 2-12; m is independently selected from 0, 1, 2, and 3; and, n is independently selected from 1, 2, and
 3. 4. A compound of claim 3, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein: X, Y, X′, Y′, X″, and Y″ are individually selected from the following: H, C₁₋₄ alkyl, halogen, CF₃, O—C₁₋₄ alkyl, NO₂, O(CH₂CH₂O)_(p)R, NR^(a)(CH₂CH₂O)_(p)R, and NR₂; Z is selected from: H, C₁₋₄ alkyl, OH, O—C₁₋₄ alkyl, acetyloxy, and propionyloxy; Q is selected from: —(CH₂)_(n)-tetrazole, —CHA(CH₂)_(m)C(O)NHR, CHA(CH₂)_(m)CO₂R, (CH₂)_(n)-phenyl-(CH₂)_(m)CO₂R, (CH₂)_(n)-phenyl-(CH₂)_(m)CONH₂, (CH₂)_(n)-phenyl-(CH₂)_(m)-tetrazole, and (CH₂CH₂O)_(p)R; M is C═O or SO₂; A is selected from H, C₁₋₄ alkyl, (CH₂)_(m)-C₃₋₆-cycloalkyl, CH₂OH, CH(CH₃)OH, (CH₂)_(m)-phenyl, wherein the phenyl is substituted with 0-3 groups selected from H, C₁₋₄ alkyl, halogen, CF₃, O—C₁₋₄ alkyl, and NO₂; R is independently selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl; p is selected from 2-12; m is independently selected from 0, 1, 2, and 3; and, n is independently selected from 1, 2, and
 3. 5. A compound of claim 1, wherein the compound is selected from the compounds of Table 1a, 1b, 1c, 1d, 2, and 3 or a stereoisomer or a pharmaceutically acceptable salt thereof.
 6. A pharmaceutical composition, comprising: a compound according to claim 1 and a pharmaceutically acceptable carrier.
 7. A method of treating a disease, comprising: administering to a mammal in need thereof a therapeutically effective amount of a compound of according to claim 1, wherein the disease is selected from obesity, diabetes, cardiometabolic disorders, and a combination thereof.
 8. The method of claim 7, wherein the cardiometabolic disorder is selected from hypertension and dyslipidemia.
 9. The method of claim 8, wherein the dyslipidemia is selected from low levels of high-density lipoprotein, high levels of low-density lipoprotein, and high levels of triglycerides.
 10. A method of treating a co-morbidity of obesity, comprising: administering to a mammal in need thereof a therapeutically effective amount of a compound of claim
 1. 11. The method of claim 10, wherein the co-morbidity is selected from diabetes, Metabolic Syndrome, dementia, and heart disease.
 12. The method of claim 10, wherein the co-morbidity is selected from hypertension; gallbladder disease; gastrointestinal disorders; menstrual irregularities; degenerative arthritis; venous statis ulcers; pulmonary hypoventilation syndrome; sleep apnea; snoring; coronary artery disease; arterial sclerotic disease; pseudotumor cerebri; accident proneness; increased risks with surgeries; osteoarthritis; high cholesterol; and, increased incidence of malignancies of the ovaries, cervix, uterus, breasts, prostrate, and gallbladder.
 13. The method of claim 7, wherein the diabetes disorder is selected from: Type 1 diabetes, Type 2 diabetes, inadequate glucose tolerance, and insulin resistance.
 14. A method of treating a disease, comprising: administering to a mammal in need thereof a therapeutically effective amount of a. a compound of according to claim 1, and b. a second therapeutic agent; wherein the disease is selected from obesity, diabetes, cardiometabolic disorders, and a combination thereof and the second therapeutic agent is useful for treating the disease.
 15. The method of claim 14, wherein the second component is selected from the appetite suppressant sibutramine and the gut lipase inhibitor orlistat.
 16. The method of claim 15, wherein the second component is useful for treating diabetes. 